Beruflich Dokumente
Kultur Dokumente
Silvia Arber
Neuronal circuit formation
in the developing spinal cord
Pico Caroni
Plasticity of neuronal circuits
Andreas Lthi
Cellular mechanisms of learning
and memory
Andrew Matus
Molecular mechanisms of
synaptic plasticity
Denis Monard
Control of endogenous extracellular
proteases in development and
brain function
Thomas Oertner
Physiology and plasticity of
individual synapses
Botond Roska
Structure and function of local
neural circuits
Silvia Arber
Neuronal circuit
formation in
the developing
spinal cord
INTRODUCTION
The innervation of neuronal targets is a precisely
timed process that requires the pathfinding of ax-
ons to specific targets, the growth and branching
of axons in the vicinity of their targets and the for-
mation of stable synaptic connections. The aim
of our studies is to understand the molecular and
mechanistic basis of the establishment of specific
neuronal connections within a circuit of intercon- GROUP LEADER
nected neurons. A deep knowledge of the logic of Silvia Arber
how neuronal circuits are assembled during de- silvia.arber@fmi.ch
velopment and which molecules are involved in the
establishment of neuronal circuits may contribute TECHNICAL/RESEARCH
to our understanding of the functioning of the ASSOCIATES
mature nervous system. Monika Mielich
We aim to elucidate the principles of neuronal Markus Sigrist
circuit formation in the developing vertebrate
spinal cord. In the spinal monosynaptic reflex cir- POSTDOCTORAL
cuit (Fig. 1), many details of early neuronal speci- FELLOWS
fication as well as mature connectivity are already Simon Hippenmeyer*
well understood. We focus mainly on the develop- Ina Kramer*
ment of motor neurons in the ventral horn of the David Ladle
spinal cord and proprioceptive afferents (Ia affer- Stan Takumi Nakanishi
ents) in dorsal root ganglia (DRG) that establish
monosynaptic connections with motor neurons. PhD STUDENTS
It is thought that many of the decisions taken by Simon Dalla Torre
these neurons during early development, when Andreas Friese
they start extending axons and dendrites, are con- Jun Lee
trolled by cell-intrinsic factors and are determined Vera Niederkofler*
even at stages before they exit the cell cycle. Dif- Rishard Salie*
ferent classes of transcription factors have been Anna Stepien
shown to control sequential steps in the differen- Eline Vrieseling
tiation hierarchy of motor neurons in the devel-
oping spinal cord. In addition to specification of UNDERGRADUATES
neurons by cell-intrinsic cues, signaling interac- Jennifer Henaghan*
tions with cues encountered by axons en route to Roland Huber
the target or from the target region itself also have Celia Lngle*
important roles in the specification of later steps Thomas Portmann*
of neuronal connectivity (Hippenmeyer et al.2004). Claudia Suenderhauf*
To unravel the cascades of molecules controlling
neuronal circuit formation, we combine gain- and
loss-of-function mouse genetics, light microscope *left the group
imaging of fluorescently labeled neuronal sub-
populations, electrophysiological analysis and gene
expression profiling.
Wild-type Mutant
A B
Fig.2. Culture of DRG
portant for the appropriate developmental func- Using genetic approaches in the mouse, we exam- isolated from wild-type em-
tion (Hippenmeyer et al. 2005). Premature ETS ined whether Runx transcription factor activity bryos (A) or mutant em-
signaling interferes with establishment of neuronal contributes to the acquisition of selective profiles bryos with premature ETS
signaling (B) cultured
projections, acquisition of terminal neuronal traits of neurotrophic factor receptor and neuropeptide
without neurotrophic sup-
and dependence on neurotrophic support (Fig. 2). expression in different subpopulations of DRG port (left) or in presence
In contrast, late expression of the identical ETS sensory neurons, traits associated with function- of NGF (right). Mutant
transcriptional regulator in the same neuronal lin- ally distinct neuronal subpopulations that ensure DRG neurons survive and
eage can substitute for ETS gene function and pro- their maturation.We found that runt domain tran- grow axons in the absence
mote neuronal differentiation. Together, the findings scription factor signaling is essential for the emer- of neurotrophic support
suggest that DRG sensory neurons undergo a tem- gence of key aspects of subpopulation character
poral developmental switch, revealed by distinct in sensory neurons, apparently by repressing alter-
responses to ETS transcription factor signaling at nate traits. Specifically, we found that Runx3 con-
sequential steps of neuronal maturation. trols the establishment of a proprioceptor pheno-
Repulsive Guidance Molecule (RGM) has been im- This work was carried out in collaboration with
plicated in the control of the topography of reti- P. Caroni (Friedrich Miescher Institute, Basel), J. A.
nal ganglion cell (RGC) axon termination zones Hassell (McMaster University, Ontario), C.E. Hen-
along the anterior-posterior axis of the chick tec- derson (Columbia University, New York), T.M. Jessell
tum. The molecular identification of RGM re- (Columbia University, New York), K. M. Murphy
cently opened the way to functional studies in the (Washington University, St. Louis), A.Pierani (Ecole
mouse. We found that there are three mouse pro- Normale Suprieure, Paris) and W. D. Snider (Uni-
teins homologous to chick RGM. Two members versity of North Carolina, Chapel Hill).
of this gene family (mRGMa and mRGMb) are ex-
Selected publications
Hippenmeyer S, Kramer I, Arber S (2004) Kramer I, Sigrist M, de Nooij JC, Salie R, Niederkofler V, Arber S (2005)
Control of neuronal phenotype: what tar- Taniuchi I, Jessell TM, Arber S (2006) Patterning molecules: multitasking in the
gets tell the cell bodies. Trends Neurosci A role for Runx transcription factor signal- nervous system. Neuron 45:189-192
27:482-488 ing in dorsal root ganglion sensory neuron
diversification. Neuron 49:379-393
Hippenmeyer S, Vrieseling E, Sigrist M,
Portmann T, Laengle C, Ladle DR, Niederkofler V, Salie R, Arber S (2005)
Arber S (2005) Hemojuvelin is essential for dietary iron
A developmental switch in the response sensing, and its mutation leads to severe
of DRG neurons to ETS transcription factor iron overload. J Clin Invest 115:2180-
signaling. PLoS Biol 3:e159 2186
INTRODUCTION
Transmission of information in the nervous sys-
tem takes place at unique intercellular contact sites,
the synapses. We investigate regulatory mecha-
nisms that control the formation, maintenance
and turnover of synaptic connections (anatomical
plasticity). We are particularly interested in dis-
covering and understanding mechanisms that de-
termine the plasticity of defined neuronal circuits, GROUP LEADER
as they may inform us about principles of learning, Pico Caroni
adaptation, and resilience to disease in the nervous pico.caroni@fmi.ch
system.
To capture specific plasticity that might go un- TECHNICAL/RESEARCH
detected using more reductionistic strategies, we ASSOCIATES
rely on detailed anatomical maps of how individ- Corinna Schneider
ual defined neurons are inserted into the circuit, Lan Xu
and on experimental approaches that allow us to
monitor and manipulate precisely defined ele- POSTDOCTORAL
ments of the circuit. FELLOWS
Applying this approach to the neuromuscular Ewa Bednarek
system, we investigate mechanisms underlying Tamara Brown*
intrinsic and age-dependent differences in the Alexandre Ferrao Santos
anatomical plasticity of defined synapses, as well Smita Saxena
as mechanisms of selective vulnerability to disease
in neurodegeneration. We find that the arrange- PhD STUDENTS
ment of neuromuscular subsystems differing in Michael Abanto
plasticity and vulnerability properties is such that Yuichi Deguchi
selective manipulation and molecular analysis are Ivan Galimberti
feasible up to the level of identified cell genomics Nadine Gogolla
and proteomics. This type of approach also guides Sharon Lefler*
our research on anatomical plasticity in the hippo- Sarah Rdiger
campus, a brain structure that plays a critical role Anirban Sadhu*
in learning and memory. We are discovering spe- Ivana Samarzija*
cific life-long synaptic rearrangements influenced Claudia Vittori
by experience in an axonal projection with major Stefan Wacha
functional significance to hippocampal function.
We apply combinations of mouse genetics, be-
havioral analysis, neuroanatomy, live imaging, tis- *left the group
sue and cell culture, cell biology, proteomics, and
single cell genomics. To visualize neurons and their
subcellular components in situ, we use transgenic
mice expressing targeted fluorescent chimeric pro-
teins in single neurons.
ticular synapses are lost selectively, gradually or NMJs were being lost according to defined albeit
abruptly, and whether it is synapses, axons or den- still unknown principles. Considering possible un-
drites that are targeted by disease. The complexi- derlying principles, one possibility seems to be that
ties of adult brain circuitry pose formidable chal- the predictable patterns of losses might reflect dif-
lenges to elucidating mechanisms of early disease ferences between MNs and/or muscle fibers. Thus,
progression. However, in animal models of moto- MNs innervating skeletal muscle fibers are subdi-
neuron (MN) disease, more accessible synapses be- vided into the functional subtypes fast fatigable
tween MNs and muscles are also lost early on and (FF), fast fatigue-resistant (FR) and slow (S), which
in reproducible patterns. MN disease models thus exhibit distinct excitability and recruitment prop-
provide uniquely advantageous systems to investi- erties and establish motor units (consisting of one
gate pathways of vulnerability and disease pro- MN and all the muscle fibers it innervates) with
gression in neurodegeneration. Such information markedly distinct fatigue and force properties.
is essential for early detection and the development We recently exploited a combination of Thy1-
of more effective treatments against these diseases. transgenic mice expressing GFP fusion proteins in
only a few neurons, together with established his-
A B tological procedures, to quantitatively map the in-
nervation of hindlimb muscle compartments by
MNs and their functional subtypes in the mouse
(Fig. 3). We then applied these maps and proce-
dures to elucidate principles and mechanisms of
early disease progression in FALS mice. Our results
identified axons of first FF and then FR MNs as
being selectively vulnerable at well-defined times
early in disease and showed that, where present, S
MN axons resist and compensate through sprout-
ing and reinnervation. Axonal vulnerability in-
Fig.3. Quantitative topo- volved absence of neurofilament adjustments,
graphic map of motor units Transgenic mice expressing human SOD1 point synaptic vesicle stalling, loss of synaptic vesicles
innervating LGC muscle mutant proteins associated with familial amy- from all peripheral synapses, and upregulation of
in mouse. A Nerves (green), otrophic lateral sclerosis (FALS) develop paralytic Bcl2A1-a in MNs; this was followed by Lactacystin-
NMJs (red), compartments
MN disease closely resembling human ALS. Mice sensitive pruning of all peripheral synapses and
(lat., int., med.) and sub-
compartments (l1-2, i1-3,
expressing high levels of human SOD1(G93A) terminal axon branches. The axonal vulnerability
m1-3) in mouse LGC. provide a particularly valuable model of FALS due process could be alleviated by peripheral applica-
B Arborization of axons to their remarkably predictable pattern of disease tions of CNTF. Since early defects in axonal trans-
mGFP (green) innervating progression. The mice develop first clinical signs port have also been associated with Alzheimer's
medial compartment of of MN disease at postnatal day (P) 80-90 and die and Huntington's disease, these findings may re-
LGC. RITC-a-Bungarotoxin at P1365. Recent studies have established that flect general principles of disease progression and
(red) visualizes all NMJs;
many peripheral synapses between MNs and mus- treatment in neurodegeneration, independent of
bar 1 mm
cles (NMJs) are lost in SOD1(G93A) mice from the molecular pathways triggering particular forms
P50 on, before detectable losses of motor axons of disease.
in ventral roots exiting the spinal cord and long
before any clinical sign of disease. In addition, a
detailed study revealed reproducible differences in
the timing of denervation of individual muscles,
and distinct topographic patterns of denervation
in individual hindlimb muscles, suggesting that
Selected publications
De Paola V, Holtmaat A, Knott G, Song S, Golub T, Caroni P (2005) Santos AF, Caroni P (2004)
Wilbrecht L, Caroni P, Svoboda K (2006) PI(4,5)P2-dependent microdomain assem- Assembly, plasticity and selective vulnera-
Cell type-specific structural plasticity of blies capture microtubules to promote bility to disease of mouse neuromuscular
axonal branches and boutons in the adult and control leading edge motility. J Cell junctions. J Neurocytol 32:849-862
neocortex. Neuron 49:861-875 Biol 169:151-165
INTRODUCTION
Experience-dependent changes in behavior are
mediated by long-term functional modifications
in brain circuits. To study the underlying synaptic
and cellular mechanisms, we are using classical
(Pavlovian) fear conditioning, a simple form of as-
sociative learning that is particularly suitable for
studying in rodents. Behavioral and in vivo elec-
trophysiological experiments suggest that associa- GROUP LEADER
tive synaptic plasticity in the lateral amygdala, a Andreas Lthi
key structure for emotional learning and memory, andreas.luethi@fmi.ch
underlies classical fear conditioning. These exper-
iments established the strongest link between sy- TECHNICAL/RESEARCH
naptic plasticity and behavioral learning described ASSOCIATES
so far in mammals. Ronald Knig*
A thorough understanding of the cellular mech- Christian Mller
anisms underlying changes in behavior requires a
detailed knowledge of the anatomical and func- POSTDOCTORAL
tional properties of the relevant neuronal network FELLOWS
elements. Principal neurons in the lateral amyg- Guillaume Casassus
dala receive converging thalamic and cortical sen- Ingrid Ehrlich
sory afferents that are simultaneously active dur- Christine Gebhardt*
ing fear conditioning. We found recently that both Francois Grenier
afferents exhibit input-specific associative synaptic Cyril Herry
plasticity mediated by distinct molecular mecha- Yann Humeau*
nisms. We are also interested in the functional role
of distinct inhibitory circuits. PhD STUDENTS
Using a combination of in vitro and in vivo elec- Stphane Ciocchi
trophysiology, imaging, molecular biology and be- Elodie Fourcaudot
havioral approaches, we investigate activity- and Karin Loretan*
experience-dependent changes in the neural cir- Verena Senn
cuitry of the mouse amygdala with the ultimate Hamdy Shaban*
goal of understanding network function and plas-
ticity subserving this simple form of associative UNDERGRADUATES
learning. Dorothea Hmmerer*
Magalie Klaey*
GUEST SCIENTIST
Heidrun Bchli*
Selected publications
Herry C, Triffilieff P, Micheau J, Lthi A, Humeau Y, Herry C, Kemp N, Shaban H, Shaban H, Humeau Y, Herry C, Casassus G,
Mons N (2006) Fourcaudot E, Bissire S, Lthi A (2005) Shigemoto R, Ciocchi, S, Barbieri S,
Extinction of auditory fear conditioning re- Dendritic spine heterogeneity determines van der Putten H, Kaupmann K, Bettler B,
quires MAPK/ERK activation in the basolat- afferent-specific Hebbian plasticity Lthi A (2006)
eral amygdala. Eur J Neurosci 24:261-269 in the amygdala. Neuron 45:119-131 Generalization of amygdala LTP and condi-
tioned fear in the absence of presynaptic
Humeau Y, Lthi A (2006) Lortan K, Bissire S, Lthi A (2004) inhibition. Nature Neuroscience
Dendritic calcium spikes induce bi-direc- Dopaminergic modulation of spontaneous 9:1028-1035
tional synaptic plasticity in the lateral inhibitory network activity in the lateral
amygdala. Neuropharmacology (in press) amygdala. Neuropharmacology 47:631-639
Andrew Matus
Molecular mechanisms
of synaptic plasticity
INTRODUCTION
With my retirement due in April 2007, this last re-
port from my group is an opportunity to reflect on
our work over the past 29 years at the FMI and to
consider what implications our results may have
for the future. Our mission has been to explore the
molecular mechanisms regulating morphological
changes in the synaptic connections of brain neu-
ronal circuits, with the ultimate aim of gaining GROUP LEADER
new insights into the cellular basis of long-term Andrew Matus
memory. We began at an obvious place by seeking aim@fmi.ch
to identify structural proteins involved in building
synapses during brain development. First, we TECHNICAL/RESEARCH
worked out methods for isolating postsynaptic ASSOCIATES
densities and, using the then new method of SDS Heike Brinkhaus
gel electrophoresis, for identifying candidate mol- Urs Mller
ecules (Walters and Matus 1975). Subsequently, we
raised specific antibodies for immunohistochem- POSTDOCTORAL
ical staining to locate sites of action of these mol- FELLOWS
ecules in the brain. Indeed the rationale for setting Martin Verkuyl
up my group at the FMI was the potential of new Pingwei Zhao*
immunohistochemical methods for solving the
mystery of how specific assemblies of proteins form PhD STUDENT
and maintain the distinctive functional structures Andreas Birbach*
of neurons their axons, dendrites and synapses.
The exploitation of emerging technologies has UNDERGRADUATES
been a constant theme in our work and a major Christian Mller*
source of the discoveries we have been fortunate Reto Zwahlen*
to make. In a wider context, it is clear that the de-
velopment of new technology platforms, ranging
from DNA sequencing to live-cell microscopy, has *left the group
been by far the most important source of novel
data in biomedical research over the past quarter
century. Indeed, the inherent flexibility of the
Friedrich Miescher Institute, as part of an inde-
pendent research foundation, remains a key ad-
vantage for the rapid adoption of cutting edge ap-
proaches.
Selected publications
Ackermann M, Matus A (2003) Fischer M, Kaech S, Knutti D, Matus A Matus A, Huber G, Bernhardt R (1983)
Activity-induced targeting of profilin and (1998) Neuronal microdifferentiation. Cold Spring
stabilization of dendritic spine morphology. Rapid actin-based plasticity in dendritic Harbor Symp Quant Biol 48:775-782
Nature Neurosci 6:1194-1200 spines. Neuron 20:847-854
Walters BB, Matus A (1975)
Birbach A, Verkuyl JM, Matus A (2006) Matus A (1988) Tubulin in postsynaptic junctional lattice.
Reversible, activity-dependent targeting Microtubule-associated proteins: their Nature 257:496-498
of profilin to neuronal nuclei. Exp Cell Res potential role in determining neuronal mor-
312:2279-2287 phology. Annu Rev Neurosci 11:29-44
INTRODUCTION
The question of the importance of extracellular
proteolytic activity for cellular behavior both in
vitro and in vivo has been neglected for a long time,
partly because of the difficulties in precisely dis-
secting complex proteolytic cascades. For example,
serine proteases activate latent forms of some met-
alloproteases that subsequently boost the activity
of other members of this family. These potent am- GROUP LEADER
plification systems degrade components of the ex- Denis Monard
tracellular matrix, trigger activation or inactiva- denis.monard@fmi.ch
tion of specific classes of receptors and generate
biologically active factors by specific cleavage of TECHNICAL/RESEARCH
their latent forms. Locally secreted inhibitors con- ASSOCIATES
trol the onset, the efficiency, and the duration of Sabrina Djaffer
these proteolytic explosions. Our group has con- Elisabeth Fries Schmid*
tributed to this field of research by characterizing Maria Rita Meins
a neurite-promoting factor as protease nexin-1 Eliza Pandini Figueiredo Moreno
(PN-1), one of, if not the most potent endogenous
serine protease inhibitor. POSTDOCTORAL
Our aim remains to dissect the in vivo relevance FELLOWS
of the adequate control of endogenous serine pro- Gianluca Civenni*
tease activity by studying mice lacking PN-1 or by Brengre Fayard
overexpressing it in neurons. To efficiently localize Anne-Catherine Feutz*
and quantitatively monitor in vivo PN-1 expres- Maria Maddalena Lino
sion, we also generated reporter mice by inserting Slobodanka Orolicki
an internal ribosomal entry site-b-galactosidase Tanuja Rohatgi
construct at the end of the PN-1 coding sequence, Catherine Vaillant Alibert
thus maintaining intact the entire 5 regulatory
region of the gene (PN-1 KI mice). PhD STUDENTS
Mirna Kvajo*
Xiaobiao Li*
UNDERGRADUATES
Cdric Fischer*
Colette Maurer*
Antonia Rosenstiel*
Hlne T*
Selected publications
De Castro Ribeiro M, Badaut J, Price M, Kvajo M, Albrecht H, Meins M, Hengst U, Luthi A, Putten H, Botteri FM, Mansuy IM,
Meins M, Bogousslavsky J, Monard D, Hirt Troncoso E, Lefort S, Kiss JZ, Petersen CCH, Meins M, Frey U, Sansig G, Portet C, Schmutz
L (2006) Monard D (2004) M, Schroder M, Nitsch C, Laurent JP, Monard
Thrombin in ischemic neuronal death. Exp Regulation of brain proteolytic activity con- D (1997)
Neurol 198:199-203 trols the function of NMDA receptors. J Neu- Endogenous serine protease inhibitor modu-
rosci 24:9734-9743 lates epileptic activity and hippocampal long-
term potentiation. J Neurosci 17:4688-4699
Li X, Herz J, Monard D (2006)
Activation of ERK signaling upon alternative
protease nexin-1 internalization mediated by
syndecan-1. J Cell Biochem (in press)
INTRODUCTION
Neurons in the brain communicate with each other
through synapses. These change their strength de-
pending on the temporal patterns of activity in
pre- and postsynaptic cells, a process thought to be
crucial for processing and storage of information
in the brain. It is not known, however, whether
all synapses change their transmission character-
istics according to the same rules. Should we view GROUP LEADER
synapses as independent units of information pro- Thomas Oertner
cessing or do neighboring synapses cooperate, e. g., thomas.oertner@fmi.ch
during induction of plasticity? Do synapses switch
between potentiated and depressed states or do TECHNICAL/RESEARCH
they display a continuum of stable states? To address ASSOCIATES
such questions, we focus on the connection be- Daniela Gerosa Erni
tween hippocampal CA3 pyramidal cells and CA1 Ursin Stauss*
pyramidal cells, a well-defined system for synaptic
plasticity. Most of these synapses are formed on POSTDOCTORAL
dendritic spines, which show a rich, dynamic di- FELLOW
versity of shape and size. The functional implica- Tobias Rose
tion of this diversity is of great interest to us.
To examine the properties of individual synapses PhD STUDENTS
in intact brain tissue, we use two-photon laser Niklaus Holbro
scanning microscopy to optically record the am- Asa Mller-Grunditz
plitude of postsynaptic calcium transients in den- Yan-Ping Zhang
dritic spines. This allows us to monitor the activ-
ity of individual, identified synapses over several UNDERGRADUATES
hundred stimulations and to measure synaptic pa- Matthew Mikulski*
rameters, e.g., the time constants of facilitation and Lei Tian*
depression. We can distinguish changes in presy-
naptic release probability from changes in the am- GUEST SCIENTIST
plitude of the postsynaptic response. At the same Jim Yu-Hsiang Tiao*
time, motility and growth of new spines can be
plotted. Acute hippocampal slices and organotypic
slice cultures of the rodent brain are used to pre- *left the group
serve the local environment of the synapses scru-
tinized. In vitro transfection techniques are also
applied to study morphology and function of gene-
tically modified neurons within a network of wild-
type cells. Optical monitoring and manipulation
of the number of fluorescently tagged proteins in
individual synapses should give insight into regu-
latory mechanisms governing synaptic transmis-
sion.
Selected publications
Nimchinsky EA, Yasuda R, Oertner TG, Oertner TG, Matus A (2004) Yasuda R, Nimchinsky EA, Scheuss V,
Svoboda K (2004) Calcium regulation of actin dynamics in Pologruto TA, Oertner TG, Sabatini BL,
The number of glutamate receptors dendritic spines. Cell Calcium 37:477-482 Svoboda K (2004)
opened by synaptic stimulation in single Imaging calcium dynamics in small
hippocampal spines. J Neurosci Oertner TG, Sabatini BL, Nimchinsky EA, neuronal compartments. Science STKE
24:2054-2064 Svoboda K (2002) 2004 (219), pl5
Facilitation at single synapses probed with
optical quantal analysis. Nature Neurosci
5:657-664
Botond Roska
Structure and function
of local neural circuits
INTRODUCTION
The function of the brain can be studied at many
different hierarchical levels. We are interested in
how neurons interact in local neuronal networks
to compute behaviorally relevant functions. We
use the mammalian retina as a model system be-
cause the input, the dynamically changing light
pattern, is well defined and can be easily manipu-
lated experimentally. Moreover, the activity of each GROUP LEADER
neuron can be recorded during retinal light stim- Botond Roska
ulation. Our experimental approach is inter-dis- botond.roska@fmi.ch
ciplinary: we combine physiological, molecular,
viral and computational approaches to reveal the TECHNICAL/RESEARCH
structure and function of retinal circuits. We use ASSOCIATES
molecular techniques to genetically identify cell Brigitte Gross Scherf
types in the network and label them using trans- Yukiko Shimada
genic technologies. The connections of labeled cells
are revealed using trans-synaptic viruses. Next we POSTDOCTORAL
study the function of a genetically isolated circuit FELLOWS
with physiological and two-photon laser imaging David Balya
tools. Finally, we use computational methods to Pamela Lagali
predict the behavior of an isolated circuit in nat- Thomas Mnch
ural conditions.
PhD STUDENTS
This brief report introduces the work of Botond Roska, Sandra Siegert
a new group leader at the FMI who arrived recently Tim Viney
from Harvard University.
UNDERGRADUATE
Volker Busskamp
GUEST SCIENTIST
Daniel Hillier
Selected publications
Balya D, Roska B (2005) Roska B, Werblin FS (2001) Roska B, Molnar A, Werblin FS (2006)
Retina model with real time implementa- Vertical interactions across ten parallel Parallel processing in retinal ganglion cells:
tion. International Symposium on Circuits stacked representations in the mammalian how integration of space-time patterns
and Systems ISCAS 2005, Kobe, Japan, retina. Nature 410:583-587 of excitation and inhibition form the spiking
pp 5222-5225 output. J Neurophysiol 95:3810-3822
Roska B, Werblin FS (2003)
Global shifts in natural scenes block spiking
in specific ganglion cell types. Nature
Neurosci 6:600-608
Rafal Ciosk
Mechanisms of totipotency in the germline
Witold Filipowicz
Mechanisms of RNA interference and
microRNA function in mammalian cells
Susan Gasser
Functional organization of the nucleus
Helge Grosshans
Regulation of animal development by
microRNAs
Patrick Matthias
Regulation of gene expression by
POU proteins, their coactivators and
chromatin regulators
Frederick Meins
Plant epigenetics and RNA silencing
Antoine Peters
Epigenetic programming in the mammalian
germ line and pre-implantation embryos
Dirk Schbeler
Dynamics and propagation of epigenetic
states
Rafal Ciosk
Mechanisms of
totipotency
in the germline
INTRODUCTION
Germline cells eventually develop into sperm and
eggs. Like embryonic stem cells, germ cells give rise
to most cell types through a property called totipo-
tency that may one day be utilized to treat degen-
erative diseases such as Parkinson or juvenile dia-
betes. Loss of totipotency in human germ cells can
result in unusual tumors called teratomas, which
are a mix of various cell types such as teeth, hair or GROUP LEADER
bone. These tumors are the most frequent cancer Rafal Ciosk
type in the ovary and also occur in testes, but little rafal.ciosk@fmi.ch
is known about how they form or how totipotency
is normally maintained in the germline. TECHNICAL/RESEARCH
We use Caenorhabditis elegans as a model system ASSOCIATE
to study these problems. In principle, maintenance Mathias Senften
of germ cell totipotency could be achieved by in-
sulating germ cells from external cues that induce PhD STUDENT
non-germ cell fates. However, when C. elegans germ Bjrn Biedermann
cells are abnormally released from the gonad,
they invade somatic tissues but maintain germ cell UNDERGRADUATE
identity. There is also evidence that germ cells are Elzbieta Kowalska
insulated from internal cues that might specify
somatic fates. A master regulator of somatic differ-
entiation in the embryo, the transcription factor
PAL-1/Caudal, is occasionally expressed in the
wild-type germline, but its expression is not suffi-
cient to induce somatic differentiation. These ob-
servations suggest that germ cells have a mecha-
nism(s) preventing inappropriate developmental
programs. Our previous recent results suggested
that two conserved KH-domain translational re-
pressors, MEX-3 and GLD-1, have partially re-
dundant functions in the germline. To test this,
we constructed a mex-3 gld-1 double mutant and
found, in addition to defects in gametogenesis, that
many gonad cells did not resemble germ cells. By
several criteria, including expression of molecular
markers and cellular morphology, these cells trans-
differentiated into various somatic cell types, in-
cluding muscles, neurons, and intestinal cells. This
worm teratoma requires entry of germ cells into
meiosis and coincides with the disappearance of
germline-specific protein/RNA structures called P
granules. Our findings implicated RNA regulation
in the maintenance of germline totipotency and
established a genetically tractable model for study-
ing teratomas.
2A OUTLOOK
Selected publications
Ciosk R, DePalma M, Priess JR (2004) Good K, Ciosk R, Nance J, Neves A, Unhavaithaya Y, Shin TH, Miliaras N, Lee J,
ATX-2, the C. elegans ortholog of ataxin 2, Hill RJ, Priess JR (2004) Oyama T, Mello C (2002)
functions in translational regulation in the The T-box transcription factors TBX-37 and MEP-1 and a homolog of the NURD
germline. Development 131:4831-4841 TBX-38 link GLP-1/Notch signaling to complex component Mi-2 act together to
mesoderm induction in C. elegans embryos. maintain germline-soma distinctions in
Ciosk R, DePalma M, Priess JR (2006) Development 131:1967-1978 C. elegans. Cell 111:991-1002
Translational regulators maintain totipo-
tency in the Caenorhabditis elegans Sheth U, Parker R (2003)
germline. Science 311:851-853 Decapping and decay of messenger RNA
occur in cytoplasmic processing bodies.
Science 300:805-808
INTRODUCTION
The epigenetic control of gene expression and post-
transcriptional silencing of genes by RNA inter-
ference (RNAi) and microRNAs (miRNAs) has
emerged recently as an extraordinarily important
and interesting area of molecular biology. These
reactions contribute significantly to the develop-
mental- and tissue specificity of gene expression.
They also exemplify the key role of hundreds of GROUP LEADER
novel non-coding RNAs in the regulation of gene Witold Filipowicz
expression. witek.filipowicz@fmi.ch
During RNAi, double-stranded RNA (dsRNA)
acts as a sequence-specific inducer of mRNA de- TECHNICAL/RESEARCH
gradation. The degradation is mediated by ~20-bp ASSOCIATES
small interfering RNAs (siRNAs) that arise by Caroline Artus
the endonucleolytic processing of dsRNA by the Tabea Zoller
RNase III enzyme Dicer (Fig.1). In their structural
properties siRNAs are related to miRNAs,a new type POSTDOCTORAL
of small ~21-nt regulator. Hundreds of miRNAs FELLOWS
are encoded in the genomes of eukaryotes as Sankar Bhattacharyya
diverse as plants and mammals. Unlike siRNAs, Suvendra Nath Bhattacharyya
which guide endonucleolytic degradation of tar- Michael Doyle
get mRNAs, miRNAs in metazoa generally imper- Maciej Drozdz*
fectly base-pair to the mRNA 3-untranslated Fabrice Kolb*
regions and inhibit protein synthesis (Fig. 1). Ramesh Pillai*
Translationally repressed mRNAs accumulate in Lanja Saleh*
cytoplasmic processing bodies, P-bodies, where Petr Svoboda
they are either stored for future reutilization or
degraded. RNAi and miRNA-mediated regulation PhD STUDENTS
are very complex reactions involving dozens of dif- Jody Filkowski
ferent proteins and intersecting with many other Astrid Haase
cellular pathways. The most intriguing connec- Lukasz Jaskiewicz
tion is that with transcriptional gene silencing, Daniela Schmitter*
TGS. Components of the RNAi machinery are Lasse Sinkkonen
involved in the control of chromatin structure Kaifu Tang*
and/or DNA methylation but details of these reac-
tions remain poorly understood, particularly in UNDERGRADUATES
mammals. Marcin Dembinski
Our research focuses on the mechanism and a Christine Ender*
biological function of RNAi and miRNAs and on Regula Habermacher
the role of the RNAi apparatus in TGS in mam- Adam Kole*
malian cells. Luca Schenk*
ROLE OF DICER IN RNAi AND miRNA REACTIONS PROTEINS INTERACTING WITH DICER AND THE
RISC ASSEMBLY
L. Jaskiewicz, M. Doyle, T. Zoller, F. Kolb
A. Haase, L. Jaskiewicz and F. Kolb, in collaboration
Dicer is a key enzyme in the RNAi and miRNA
with T. Hobman (University of Alberta Edmonton) and
pathways required for the biogenesis of both com-
A. Gatigniol (McGill University, Montreal)
ponents. Human Dicer is a large ~220 kDa multi-
domain protein. It contains RNA helicase/ATPase, Several proteins interacting with Dicer have been
DUF283 and PAZ domains, two neighboring identified. These include members of the Argonaute
RNase III-like domains (RIIIa and RIIIb), and a family, small proteins containing two dsRNA Bind-
C-terminal dsRNA-binding domain (dsRBD). The ing Domains (dsRBDs) and the ortholog of human
RNase III domains resemble the catalytic domain Fragile X Mental Retardation protein, dFMR1, in
of the bacterial RNase III, which also has specificity Drosophila. More recently, Dicer was also found to
for dsRNA. Our previous work with different mu- be the core component of RISC essential for mRNA
tants of Dicer indicated that the enzyme functions target cleavage. The Argonaute family is highly
as an intramolecular dimer of RIIIa and RIIIb conserved in most eukaryotes and is divided into
domains, assisted by two RNA-binding domains, two subgroups: Ago and Piwi/Hiwi. Ago proteins
dsRBD and PAZ, the latter being involved in the are components of RISC, mediating gene silencing
recognition of the 3-overhang end. Contrary to through mRNA cleavage and translational repres-
previous speculation, we found that Dicer has only sion. The PAZ domains of the Ago and Dicer pro-
teins were originally thought to mediate their in-
teraction. However, we have found that it is the
PIWI domain of human proteins hAgo2 and Hiwi
that binds directly to the Dicer RNase III domain.
To identify new proteins associating with Dicer,
we raised monoclonal and polyclonal antibodies
against human Dicer. The antibodies, which effi-
ciently immunoprecipitate Dicer from extracts of
different cultured cells, were used to identify inter-
acting proteins by combining two-dimensional gel
electrophoresis and mass spectrometry. We identi-
fied TRBP [HIV-1 transactivating response (TAR)
RNA-binding protein] as a protein partner of hu-
man Dicer and demonstrated it to be essential for
optimal RNA silencing mediated by siRNAs and
endogenous miRNAs. Previously TRBP, which
contains three dsRBD domains, has been assigned
several different functions, including inhibition
Fig.1. Schematic represen-
one processing center containing two independent of the interferon (IFN)-induced dsRNA-regulated
tation of RNAi and miRNA
pathways
RNA cleavage sites and generating products with protein kinase PKR, modulation of HIV-1 gene
2-nt 3-overhangs.Various mutants of Dicer are now expression, and control of cell growth. The TRBP-
being used to characterize its in vivo and in vitro Dicer interaction now established raises the possi-
interactions with other proteins participating in bility of cross-talk between RNAi and the IFN/PKR
the assembly of the RNA-induced silencing com- pathways. We are using immunoprecipitation and
plex (RISC; Fig. 1), such as Argonaute (Ago) and other approaches to identify additional proteins
TRBP. Using purified recombinant Dicer, we found interacting with Dicer. We are also mapping the
that the enzyme also binds to siRNAs in vitro (col- interaction between Dicer, Ago and TRPB, and use
laboration with Erik Sontheimer, Northwestern recombinant proteins in experiments aimed at the
University, Evanston, Illinois), consistent with the reconstitution of the catalytically active RISC com-
idea that Dicer plays a role in downstream steps of plex.
RNAi in addition to its processing function. Pre-
vious cell fractionation and immunolocalization ROLE OF RNAi MACHINERY IN CHROMATIN
experiments indicated that Dicer resides mainly SILENCING IN MAMMALS
in the cytoplasm. However, the reported involve-
P. Svoboda, L. Sinkkonen and T. Zoller, in collabo-
ment of RNAi machinery in chromatin transac-
ration with R. Schultz (University of Pennsylvania,
tions prompted us to re-investigate the localization
Philadelphia)
of Dicer and other RNAi components in mam-
malian cells. In various organisms, factors involved in RNAi also
participate in the formation and maintenance of
heterochromatin and in TGS. This connection,
Selected publications
Bhattacharyya S, Habermacher R, Haase A, Jaskiewicz L, Zhang H, Lain S, Zhang H, Kolb FA, Jaskiewicz L, Westhof E,
Martine U, Closs EI, Filipowicz W (2006) Sack R, Gatignol A, Filipowicz W (2005) Filipowicz W (2004)
Relief of microRNA-mediated translational TRBP, a regulator of cellular PKR and Single processing center models for
repression in human cells subjected to HIV-1 virus expression, interacts with Dicer human Dicer and bacterial RNase III. Cell
stress. Cell 125:1111-1124 and functions in RNA silencing. EMBO Rep 118:57-68
6:961-967
Filipowicz W (2005)
RNAi: the nuts and bolts of the RISC ma- Pillai R, Bhattacharyya S, Artus C,
chine. Cell 122:17-20 Zoller T, Cougot N, Basyuk E, Bertrand E,
Filipowicz W (2005)
Inhibition of translational initiation by
let-7 microRNA in human cells. Science
309:1573-1576
INTRODUCTION
My laboratory pursues two general research themes.
The first concerns epigenetic regulation of gene
expression and genome duplication. Our area of
expertise is the long-range three-dimensional or-
ganization of chromatin in the interphase nucleus
and the impact of such structural aspects on in-
herited patterns of gene expression. The second
theme is that of genome instability during DNA GROUP LEADER
damage. Here we focus on double-strand breaks Susan Gasser
and replication fork instability, which impose con- susan.gasser@fmi.ch
trols over cell cycle progression through checkpoint
signaling. The link between the two themes is our TECHNICAL/RESEARCH
commitment to combine genetic systems with ASSOCIATES
quantitative live imaging techniques. Our geneti- Razel Arpagaus
cally tractable model organism was initially bud- Vronique Kalck
ding yeast but now includes the worm Caenorhab- Thierry Laroche*
ditis elegans. Important insights arising during the Monique Thomas
last two years are summarized below. Monika Tsai-Pflugfelder
POSTDOCTORAL
FELLOWS
Jennifer Cobb*
Olivier Fritsch*
Pierre Meister
Brietta Pike
Kenji Shimada
Angela Taddei*
Haico Van Attikum
Elisa Varela Sanz
PhD STUDENTS
Ruchi Chauhan
Anna Maria Friedel
Lutz Gehlen
Fabrizio Martino
Shigeki Nagai
Thomas Schleker
Heiko Schober
UNDERGRADUATES
Sabine Rohner*
GUEST SCIENTISTS
Yukako Oma*
Takahito Yoshida*
Selected publications
Cobb JA, Schleker T, Rojas V, Bjergbaek L, Cubizolles F, Martino F, Perrod S, Taddei A, Van Houwe G, Hediger F, Kalck V,
Tercero JA, Gasser SM (2005) Gasser SM (2006) Cubizolles F, Schober H, Gasser SM (2006)
Replisome instability, fork collapse and A homotrimer-heterotrimer switch in Sir2 Nuclear pore association confers optimal
gross chromosomal rearrangements arise structure differentiates rDNA and telomeric expression levels for an inducible yeast
synergistically from Mec1 kinase and silencing. Mol Cell 21:825-836 gene. Nature 441:774-778
RecQ helicase mutations. Genes Dev
19:3055-3069 Gartenberg MR, Neumann FR, Laroche T, van Attikum H, Fritsch O, Hohn B,
Blaszczyk M, Gasser SM (2004) Gasser SM (2004)
Sir-mediated repression can occur indepen- INO80 recruitment by H2A phosphorylation
dently of chromosomal and subnuclear links ATP-dependent chromatin remodeling
contexts. Cell 119:955-967 with DNA double-strand break repair.
Cell 119:777-788
INTRODUCTION
MicroRNAs (miRNAs) constitute a large family of
noncoding RNAs that regulate the expression of
numerous target genes in plants and animals. In-
dividual miRNAs have been implicated in diverse
developmental processes such as cell differentia-
tion, apoptosis, and stem cell division.
Using the nematode Caenorhabditis elegans as a
model system, we explore the basic biology of an- GROUP LEADER
imal miRNAs. We are particularly interested in the Helge Grosshans
let-7 miRNA, which controls terminal differentia- helge.grosshans@fmi.ch
tion of certain cells in C.elegans. In humans, where
the developmental role of let-7 is unknown, let-7 TECHNICAL/RESEARCH
has been implicated in cancer. Strikingly, lessons ASSOCIATE
learnt from C. elegans can be directly relevant to Monika Fasler
our understanding of human biology and disease.
For instance, we identified several novel, physio- POSTDOCTORAL
logically important targets of C. elegans let-7 em- FELLOW
ploying a combination of computational sequence Ingo Bssing
analysis and experimentation. Based on this work,
we subsequently identified the RAS proto-oncogene PhD STUDENT
as a target of human let-7 miRNA and gathered Xavier Ding
evidence implicating let 7 as a tumor suppressor
gene in the lung. UNDERGRADUATE
We are investigating let-7 as both an important Keovilay Chanthavinout
developmental regulator and a model miRNA. To
understand let-7 function and, thus, to learn about
miRNA biology in general, we are identifying co-
factors, targets, regulators, and biogenesis factors
of this miRNA. At the same time, we have begun
to investigate additional miRNAs implicated in de-
velopmental regulation.
THE C. ELEGANS let-7 microRNA REGULATES pressed in the seam cells or the intestine. We chose
SEVERAL TARGET GENES AT THE LARVAL- these tissues as they are sites of endogenous let-7
TO-ADULT TRANSITION expression, allowing us to avoid ectopic (over-)ex-
pression of the miRNA. In all five cases, the reporter
H. Grosshans and F.J. Slack, in collaboration with
gene was efficiently down-regulated in the presence
T. Johnson and M. Gerstein (Yale University, New Haven)
of wild-type but not mutant let-7 (Fig. 2).
After hatching, the nematode C. elegans develops The new target genes are mostly transcription fac-
through four larval stages before entering the sex- tors, including the nuclear hormone receptor daf-12
ually mature, adult stage. Major changes occur in and the forkhead transcription factor pha-4/hnf-3.
many tissues at the larval-to-adult transition; this is Strikingly, let-7 has the potential to coordinate de-
known as the larval-to-adult (L/A) switch.Through velopmental decisions across multiple tissues, as it
forward genetics, the let-7 microRNA (miRNA) has acts in at least three tissues (seam cells, intestine,
been identified as a key factor in the regulation of and ventral nerve cord) to regulate different tran-
this event. For instance, a subset of epidermal cells scription factors and cell signaling molecules. We
called the seam cells divide in a stereotypic, stem- are now working towards identifying the full com-
cell-like pattern during larval development, but plement of let-7 target genes using computational,
exit the cell cycle and fuse at the L/A transition. genetic, and candidate gene approaches. This work
Lack of let-7 prevents terminal seam cell differen- is the basis for understanding the function of let-7
tiation so that these cells re-iterate larval develop- in terminal cell differentiation and the L/A switch.
mental programs and continue to divide.
let-7 is first expressed during late larval devel- Let-7 REGULATES THE RAS PROTO-ONCOGENE
opment, resulting in repression of the lin-41 and IN C. ELEGANS AND HUMANS
hbl-1 target genes through an antisense mechanism
H. Grosshans, S.M. Johnson and F.J. Slack, in collab-
(Fig. 1). In the absence of functional let-7, its tar-
oration with J. Shingara, M. Byrom, R. Jarvis, A. Cheng,
get genes are overexpressed, preventing correct ex-
E. Labourier and D. Brown (Ambion, Austin, USA)
ecution of the L/A switch. The observation that
inactivation of lin-41 or hbl-1 through mutation Some miRNAs are highly conserved in sequence in
or RNAi can partially suppress let-7 mutant phe- different animals. One example is let-7, which is
notypes demonstrates the physiological impor- identical in C. elegans and humans. While let-7 is
tance of their regulation by let-7. known to control terminal differentiation of a sub-
set of epidermal cells in C.elegans, its role in human
development is not understood. However, recent
work has implicated human let-7 in lung cancer.
Our computational sequence analysis had pre-
dicted let-60/ras as a target of C. elegans let-7. We
validated this target by demonstrating that knock-
down of let-60/ras by RNAi suppresses let-7 mutant
phenotypes and that its 3UTR is sufficient to reg-
ulate the expression of a reporter gene in a let-7-
dependent manner.
let-60/ras is homologous to the human RAS
oncogene and we observed that the RAS 3UTR
Fig.1. An miRNA (let-7; also contains putative let-7 binding sites. Experi-
blue) recognizes partially We exploited the fact that let-7 binds to partially mental validation for RAS as a let-7 target was pro-
complementary sites in complementary sequences in its target mRNAs vided by our observation that modulation of let-7
the 3' untranslated region (Fig. 1) by using computational sequence analysis levels affected RAS expression in vitro. Moreover,
(UTR) of target mRNA
to predict additional let-7 targets. The resulting a reporter gene carrying only the 3UTR of RAS
(lin-41; black). Binding to
target mRNA prevents ac-
candidate target list was queried for suppression of was similarly responsive to altered let-7 levels.
cumulation of the encoded the let-7 phenotypes to identify physiologically im- To examine the relevance of this observation in
protein by a poorly charac- portant targets through genetic interaction with vivo, we assessed let-7 expression in human tu-
terized mechanism (?), let-7. Using RNAi, we found that ten further genes mors. Expression of let-7 was lower in lung tumors
perhaps involving inhibition in addition to lin-41 and hbl-1 could suppress let-7 than in normal lung tissue from the same patients,
of translation mutant phenotypes. indicating that let-7 targets may be overexpressed
The putative let-7 binding sites of the novel let-7 in these tumors. Consistent with this notion, we
targets are located in the 3 untranslated regions found that the tumors underexpressing let-7 also
(UTRs) of the target transcripts. To demonstrate overproduced RAS protein. As RAS is an impor-
that these 3UTRs are sufficient to induce let-7- tant oncogene in the lung, our work suggests that
dependent target gene regulation, we individually let-7 functions as a tumor suppressor gene in the
fused five of these sequences to reporter genes ex- lung by regulating RAS expression.
Selected publications
Grosshans H (2006) Grosshans H, Slack FJ (2002) Johnson SM, Grosshans H, Shingara J,
An in vivo perspective on microRNAs: Micro-RNAs: small is plentiful. J Cell Biol Byrom M, Jarvis R, Cheng A, Labourier E,
lessons from the worm. In: Clarke NJ, 156:17-22 Reinert KL, Brown D, Slack FJ (2005)
Sanseau PX (eds) MicroRNAs: biology, RAS is regulated by the let-7 microRNA
function and expression. DNA Press, Grosshans H, Johnson T, Reinert KL, family. Cell 120:635-647
Eagleville, USA (in press) Gerstein M, Slack FJ (2005)
The temporal patterning microRNA let-7
regulates several transcription factors at
the larval to adult transition in C. elegans.
Dev Cell 8:321-330
Patrick Matthias
Regulation of gene
expression by POU proteins,
their coactivators
and chromatin regulators
INTRODUCTION
The complex interplay between signal transduc-
tion cascades and genetic hierarchies of transcrip-
tion factors forms a molecular code that is unique
to each cell-type and defines its properties and fate.
In this context, our laboratory studies the mecha-
nisms of cell-specific gene expression in a geneti-
cally tractable system and concentrates on the trans-
criptional and epigenetic control of lymphoid cell GROUP LEADER
development and function (Fig. 1). We study sev- Patrick Matthias
eral transcription regulators that play a role in this patrick.matthias@fmi.ch
process, such as the POU family transcription fac-
tors Oct-1 and Oct-2 and their coactivator OBF-1. TECHNICAL/RESEARCH
It is a goal of the laboratory to understand the mode ASSOCIATES
of regulation and the respective biological roles of Chun Cao
these factors, as well as their mechanisms of action. Gabriele Matthias
Previous studies from our group have identified Adam Mizeracki*
several critical functions of OBF-1 for the normal
development and function of the lymphoid system. POSTDOCTORAL
In a second complementary direction we analyse FELLOWS
proteins involved in chromatin regulation and in Boris Bartholdy*
particular in the control of acetylation. Evidence Fabien Cubizolles
has accumulated that acetylation of histones rep- Camille Du Roure
resents a crucial epigenetic annotation of chro- Markus Kaller
matin that contributes significantly to the regula- Alexander Karnowski*
tion of gene expression. In addition, non-histone Yu Zhang*
protein acetylation plays a role in an increasing
range of cellular processes. Histone deacetylases PhD STUDENTS
(HDACs) remove acetyl groups from histone N Alain Bordon
terminal tails -as well as from other proteins- and Mathieu Dalvai
thereby contribute to the formation of a more con- So Hee Kwon
densed chromatin and to the modulation of gene Teppei Yamaguchi
expression. However, the biological role of HDACs
in mammals is still poorly understood, but it is clear UNDERGRADUATES
that these proteins are deregulated in many forms Frederick Vath*
of cancer. Recent findings suggest that HDACs also Matthias Wrobel*
play a role in other diseases. Thus, they represent
valuable potential therapeutic targets. GUEST SCIENTIST
To investigate the function of these different reg- Fatima Cavaleri*
ulatory proteins, we use a broad range of methods,
including generation and analysis of transgenic or
conditionally targeted mice together with molecu- *left the group
lar biology, biochemistry, functional genomics and
proteomics.
Selected publications
Matthias P, Rolink AG (2005) Sun J, Matthias G, Mihatsch MJ, Zhang Y, Gilquin B, Khochbin S, Matthias P
Transcriptional networks in mature and Georgopoulos K, Matthias P (2003) (2006)
developing B cells. Nature Rev Immunol Lack of the transcriptional coactivator Two catalytic domains are required for
5:497-508 OBF-1 prevents the development of protein deacetylation. J Biol Chem
systemic lupus erythematosus-like pheno- 281:2401-2404
Bartholdy B, Du Roure C, Bordon A, types in Aiolos mutant mice. J Immunol
Emsli D, Corcoran LM, Matthias P (2006) 170:1699-1706 Zhang Y, Li N, Caron C et al. (2003)
The Ets factor Spi-B is a direct critical HDAC-6 interacts with and deacetylates
target of the coactivator OBF-1. Proc Nat tubulin and microtubules in vivo.
Acad Sci USA (in press) EMBO J 22:1168-1179
INTRODUCTION
During development, cells and tissues become
progressively committed to specific fates. This re-
markable process, called determination, results
from epigenetic modifications, i.e., stable but po-
tentially reversible alterations in gene expression.
Epigenetic states can be inherited by somatic cells
and in cases such as genomic imprinting and
epimutation are even transmitted to the next sex- GROUP LEADER
ual generation. Epigenetic mechanisms involving Frederick Meins Jr.
DNA methylation, chromatin modification, and frederick.meins@fmi.ch
RNA silencing are important in human diseases,
including cancer, and play a key role in the mainte- TECHNICAL/RESEARCH
nance of genomic integrity, defense against viruses, ASSOCIATES
and transgenerational inheritance. We exploit the Jrme Ailhas
powerful advantages of Arabidopsis genetics to elu- Estelle Arn
cidate epigenetic mechanisms conserved in both Martin Regenass*
plants and animals. Heike Schley*
Our major interest is RNA silencing, which refers
collectively to RNA cleavage, translational repres- POSTDOCTORAL
sion, and DNA methylation guided by ca. 21-26 nu- FELLOWS
cleotide-long small RNAs (smRNAs). These smR- Konstantina Boutsika Muckenschnabel
NAs are generated by Dicer or Dicer-like (DCL) Quanan Hu*
activities from large, double-stranded RNAs (dsR- Corinne Keichinger*
NAs) or stem-loop precursors. Plants have evolved Azeddine Si-Ammour
a network of redundant RNA-silencing pathways Franck Vazquez
with dedicated functions and coordinate regula-
tion (Fig. 1). The small interfering RNA (siRNA) PhD STUDENTS
or RNA interference (RNAi) pathway functions Todd Blevins
primarily in defense against foreign nucleic acids and Claudia Kutter
viruses. Endogenous microRNA (miRNA), trans- Yang Ping Lee
acting siRNA (tasiRNA), and natural antisense
siRNA (nasiRNA) pathways help regulate develop- UNDERGRADUATES
ment, hormonal signaling, and stress responses. Fi- Simona Bieri
nally, the repeat-associated siRNA (rasiRNA) path- Maja Brenner*
way targets RNA-directed methylation (RdDM) of Sina Henrichs*
DNA repeats implicated in transcriptional gene Elzbieta Kowalska*
silencing (TGS) and epigenetic regulation of chro- Adrian Lutz*
matin. During the past two years, we have identified Magali Perret
mutants and novel smRNAs that provide insight Dominik Ziegler*
into how these pathways function in development,
virus defense, and epigenetic inheritance.
*left the group
NOVEL ARABIDOPSIS MUTANTS AFFECTING and esi2 mutants infected with CMV show that an
RNAi, VIRUS DEFENSE AND miRNA REGULATION endogenous, silencing-suppression pathway exists
in Arabidopsis. This pathway is activated by CMV
K. Boutsika, F. Vazquez, E. Arn, J. Ailhas
2b, requires ESI2, and is down-regulated by ESI1.
and E. Kowalska, in collaboration with F. Di Serio
(Istituto di Virologia Vegetale, CNR, Bari, Italy)
PRODUCTION OF siRNAs DERIVED FROM
We are functionally characterizing EMS loss-of- DNA VIRUSES
function mutations of five Arabidopsis ESI genes
T. Blevins, A. Si-Ammour and C. Kutter,
that result in spontaneous, constitutive RNAi of
in collaboration with T. Hohn and M. Pooggin
a green fluorescent protein reporter gene. ESI1 en-
(University of Basel)
codes a 5 3 exonuclease, XRN4, that helps de-
grade 3-fragments generated by miRNA/siRNA- The Arabidopsis Dicer-like genes DCL1-DCL4
guided cleavage of mRNA.Intriguingly, esi1 mutants and the putative RNA-dependent RNA polymerase
show pronounced variation in fertility, organ genes RDR2 and RDR6 are believed to have dedica-
placement, and organ number, suggesting that ESI1 ted functions in specific silencing pathways (Fig.1).
has an important role in developmental home- Our studies of deficiency mutants infected with the
DNA viruses, Cauliflower Mosaic Virus (CaMV)
and Cabbage Leaf Curl Virus (CaLCuV), assign
functions to all known Dicer-like activities in the
production of viral siRNAs. DCL4, DCL2, and
DCL3 are required for biogenesis of 21-, 22- and
24-nt viral siRNAs, respectively; whereas, DCL1,
which is a component of the miRNA pathway, is
required for processing of 21-nt siRNAs from a
highly structured viral RNA. Accumulation of
viral siRNAs was not affected in rdr2 or rdr6
mutants, indicating that RDR2-DCL3 and RDR6-
DCL4 are not obligate partners for siRNA biogen-
esis. None of the dcl mutants showed increased
susceptibility to CaMV or CaLCuV. Apparently, re-
dundant RNA-silencing pathways for viral defense
exist or RNA silencing is not sufficient for defense
against these viruses.
Selected publications
Akbergenov R, Si-Ammour A, Blevins T, Di Serio F, Schb H, Iglesias A, Tarina C, Klahre U, Crt P, Leuenberger SA,
Amin I, Kutter C, Vanderschuren H, Bouldoires E, Meins F Jr (2001) Iglesias VA, Meins F Jr (2002)
Zhang P, Gruissem W, Meins F Jr, Hohn T, Sense- and antisense-mediated gene silenc- High molecular weight RNAs and small
Pooggin MM (2006) ing in tobacco is inhibited by the same viral interfering RNAs induce systemic posttran-
Molecular characterization of gemini- suppressors and is associated with accumu- scriptional gene silencing in plants.
virus-derived small RNAs in different plant lation of small RNAs. Proc Natl Acad Sci Proc Natl Acad Sci USA 99:11981-11986
species. Nucl Acids Res 34:462-471 USA 98:6506-6510
Meins F Jr, Si-Ammour A, Blevins T (2005)
Glazov E, Phillips K, Budziszewski GJ, RNA silencing systems and their relevance
Schb H, Meins F Jr, Levin JZ (2003) to plant development. Annu Rev Cell Dev
A gene encoding an RNase D exonu- Biol 21:297-318
clease-like protein is required for posttran-
scriptional silencing in Arabidopsis.
Plant J 35:342-349
Antoine Peters
Epigenetic programming
in the mammalian germ
line and pre-implantation
embryos
INTRODUCTION
In mammals, the generation of totipotent embry-
onic cells from two distinct and highly differenti-
ated gametes is a prerequisite for successful devel-
opment. Totipotency enables embryonic cells to
proliferate and ultimately differentiate into a mul-
titude of distinct cell types, each with specialized
functions. The identity of each of these descendant
cells results from the interplay between transcrip- GROUP LEADER
tion factor-based and epigenetic regulatory mech- Antoine Peters
anisms translating the genetic information and antoine.peters@fmi.ch
directing somatic development.
Nuclear transfer experiments demonstrate that TECHNICAL/RESEARCH
genome-wide epigenetic marks characteristic of a ASSOCIATE
fully differentiated nucleus can be reset in a pre- Frdric Zilbermann
implantation embryo. The low developmental suc-
cess rate of such cloned embryos, however, under- POSTDOCTORAL
scores the efficacy of epigenetic erasure and sub- FELLOWS
sequent programming of parental genomes natu- Philip Hublitz
rally occurring during male and female gametoge- Pawel Pelczar*
nesis. For DNA methylation, genome wide patterns Rmi Terranova
are erased and reset during early germ cell and pre- Shihori Yokobayashi
implantation embryonic development. Similarly,
other epigenetic marks like histone methylation and PhD STUDENTS
acetylation as well as chromatin-associated factors Urszula Brykczynska
undergo extensive changes during early gameto- Eszter Posfai
genesis and embryogenesis. Mareike Puschendorf
Using conditional mouse mutants, we study the Tianke Wang
in vivo role of various histone and DNA methyl-
transferases and histone deacetylases for epigenetic UNDERGRADUATES
programming in primordial germ cells, maturing Anthony Kelly*
oocytes, developing male germ cells and pre-im- Carolin Kolb
plantation embryos. In particular, we aim to de-
termine the level of the maternal and paternal con- *left the group
tributions of certain epigenetic modifications for
regulating genome-wide activation of gene tran-
scription in the two-cell embryo and directing cell
fate decisions during subsequent pre-implantation
embryonic development. These studies will contri-
bute to our understanding of the regulatory role of
chromatin in defining and maintaining pluripo-
tency versus directing differentiation, in condi-
tions of health and disease.
Selected publications
Peters AHFM, Schbeler D (2005) Peters AHFM, Mermoud JE, O'Carroll D, Peters AHFM, O'Carroll D, Scherthan H,
Methylation of histones: playing Memory Pagani M, Schweizer D, Brockdorff N, Mechtler K, Sauer S, Schfer C,
with DNA. Curr Opin Cell Biol 17:230-238 Jenuwein T (2002) Weipoltshammer K, Pagani M, Lachner M,
Histone H3 lysine 9 methylation is an Kohlmaier A, Opravil S, Doyle M, Sibilia M,
Peters AHFM, Kubicek S, Mechtler K, epigenetic imprint for facultative hetero- Jenuwein T (2001)
O'Sullivan R, Derijck AAHA, Perez-Burgos L, chromatin. Nature Genetics 30:77-80 Loss of the Suv39h histone methyltrans-
Kohlmaier A, Opravil S, Tachibana M, ferases impairs mammalian heterochromatin
Shinkai Y, Martens JHA, Jenuwein T (2003) and genome stability. Cell 107:323-337
Partitioning and plasticity of repressive
histone methylation states in mammalian
chromatin. Mol Cell 12:1577-1589
INTRODUCTION
Chromatin is the complex of DNA and proteins in
which the genetic material is packaged inside the
cells of organisms with nuclei. Regulatory signals
entering the nucleus encounter chromatin and
the rate-limiting biochemical responses that lead
to activation of gene expression involve alterations
in chromatin structure. Nucleosomal histones are
highly modified at multiple residues and their GROUP LEADER
modification status appears to be connected with Dirk Schbeler
a variety of measurable characteristics of a gene lo- dirk@fmi.ch
cus, such as DNA methylation and timing of DNA
replication. Such epigenetic information can re- TECHNICAL/RESEARCH
strict or enhance sequence-specific recognition of ASSOCIATE
DNA and, thus, manifests a plastic epigenome that Christiane Wirbelauer
specifies cellular responses to external and internal
cues. Current models suggest that this epigenetic POSTDOCTORAL
information specifies cellular identity and potency FELLOWS
and that it behaves dynamically during cellular dif- Tim-Christoph Roloff
ferentiation and transformation. Indeed misregu- Michal Weber
lation of proteins involved in epigenetic regulation
of chromatin and DNA have been linked to many PhD STUDENTS
human diseases, including cancer. Stan Oliver Bell
Our research is aimed at understanding the hier- Fabio Mohn
archy and crosstalk between different constituents Michaela Schwaiger
of epigenetic information, their maintenance and
the regulation of reprogramming events. UNDERGRADUATES
The many players involved in epigenetic regula- Elena Aritonovska
tion point to a complex and intertwined regulatory Ozren Bogdanovic*
network, as exemplified by the increasing number David Wittig*
of described covalent histone modifications. Using
Drosophila and mammalian cellular models, we *left the group
combine a molecular approach with a genome-wide
experimental readout using DNA microarrays.
This enables us to describe the epigenome and its
dynamics in an unbiased and comprehensive fash-
ion. Our goal is to understand the control of epi-
genetic gene regulation and its role in cellular re-
programming events that occur during develop-
ment and disease.
CHROMATIN STATES AND CHROMATIN MODIFIERS gene followed by the incorporation of nucleosomes
AT ACTIVE GENES containing H3.3 (Wirbelauer et al. 2005). However,
the tested euchromatic histone modifications
C. Wirbelauer, O. Bell, E. Aritinovska
showed a bias towards the 5 end distinct from that
A large number of histone modifications have been of H3.3 (Fig. 1) and we hypothesize that H3.3 does
described recently. These are assumed to be in- not predetermine chromatin states but serves as a
volved in all DNA-templated events, yet we are only system to regain nucleosomal density following
just beginning to understand their individual and transcription-coupled displacement.
combinatorial functions. Is the encoded informa- Our current efforts are aimed at studying the
tion used to direct gene activity to particular genes? individual contribution of chromatin marks on ac-
Or does it recruit enzymatic activity that is gener- tive genes and we have started to analyze the function
ally coupled to processes such as transcription, and distribution of the methylation of lysine 36 of
replication or DNA repair? To gain insights into histone H3. This modification is also enriched at all
active genes but it is enriched downstream of the
A promoter and is linked to the process of chromatin
compaction following nucleosomal disruption by the
polymerase. We have cloned the enzymes respon-
sible for lysine 36 methylation in Drosophila and are
currently defining their function in vitro and in vivo.
Selected publications
Schbeler D (2006) Weber M, Davies JJ, Wittig D, Oakeley EJ, Wirbelauer C, Bell O, Schbeler D (2005)
Dosage compensation in high resolution: Haase M, Lam WL, Schbeler D (2005) Variant histone H3.3 is deposited at sites
global up-regulation through local recruit- Chromosome-wide and promoter-specific of nucleosomal displacement throughout
ment. Genes Dev 20:749-753 analyses identify sites of differential DNA transcribed genes while active histone mod-
methylation in normal and transformed ifications show a promoter-proximal bias.
Schbeler D, MacAlpine DM, Scalzo D, human cells. Nature Genet 37:853-862 Genes Dev 19:1761-1766
Wirbelauer C, Kooperberg C, van Leeuwen F,
Gottschling DE, O'Neill LP, Turner BM, White EJ, Emanuelsson O, Scalzo D,
Delrow J, Bell SP, Groudine M (2004) Royce T, Kosak S, Oakeley EJ, Weissman S,
The histone modification pattern of active Gerstein M, Groudine M, Snyder M,
genes revealed through genome-wide Schbeler D (2004)
chromatin analysis of a higher eukaryote. DNA replication-timing analysis of human
Genes Dev 18:1263-1271 chromosome 22 at high resolution and
different developmental states. Proc Natl
Acad Sci USA 101:17771-17776
Joy Alcedo
Neural mechanisms that influence
the aging process
Ruth Chiquet
Cell communication in growth control
and differentiation
Brian A. Hemmings
Protein kinase function in development
and cancer
Jan Hofsteenge
Molecular and functional aspects of
covalent protein modifications
Nancy Hynes
The molecular basis of breast cancer
Yoshikuni Nagamine
Regulation of the plasminogen
activator system with emphasis on
the DExH helicase RHAU
Joy Alcedo
Neural mechanisms
that influence
the aging process
INTRODUCTION
Aging is a multi-factorial process that involves
an interaction between the environment and the
gene activities of an animal. This interaction ap-
pears to be mediated by the sensory system, since
we have found that the lifespan of the nematode
Caenorhabditis elegans is influenced by both mu-
tations and treatments that inhibit the function
of its sensory neurons. We have shown that defects GROUP LEADER
in specific sensory neurons extend lifespan and Joy Alcedo
that the ability of some of these neurons to inhibit joy.alcedo@fmi.ch
longevity depends, surprisingly, on the activities
of other sensory neurons that promote longevity. TECHNICAL/RESEARCH
We have also shown that these neurons influence ASSOCIATES
lifespan through signaling pathways that control Martin Regenass
animal physiology. Indeed, one of these pathways, Monique Thomas
the insulin/IGF-1 signaling pathway, has been pro-
posed to act on the aging process by coordinately POSTDOCTORAL
regulating the expression of many genes affecting FELLOW
animal longevity. Thus, through its sensory system Wolfgang Maier
modulating the activities of pathways like insulin/
IGF-1 signaling, it is possible that the animal has PhD STUDENTS
devised a relatively rapid means to adjust its rate of Bakhtiyor Adilov
aging in response to the quality of its environment. Astrid Kleinert
Just how the sensory system elicits physiological Ivan Ostojic
changes that ultimately determine animal lifespan
is at present unclear. By using a combination of UNDERGRADUATE
genetic, cellular and molecular approaches, we Collin Ewald
plan (1) to identify sensory and neuroendocrine
pathways that influence lifespan, (2) to determine
whether the sensory control of lifespan involves
circuits at the neuronal and/or non-neuronal lev-
els, and (3) to examine whether these mechanisms
are conserved in other animals. Our finding that
putative sensory genes influence lifespan provides
an excellent opportunity to elucidate this process.
THE TEMPORAL REQUIREMENT FOR THE SENSORY THE SENSORY INFLUENCE ON LIFESPAN
INFLUENCE ON LIFESPAN APPEARS TO BE CONSERVED IN DROSOPHILA
J. Alcedo and W. Maier, in collaboration with I. Ostojic and J. Alcedo, in collaboration with W. Boll
C. Kenyon (University of California, San Francisco) and M. Noll (University of Zurich)
In addition to determining which cells are involved, Many biological processes have been conserved
we will also define the critical period during an an- between the worm and higher organisms. For ex-
imal's life when its sensory system can influence ample, the insulin/IGF-1 pathway also regulates
lifespan. To do this, we have been using a temper- the lifespan of flies and mice. Furthermore, in
ature-sensitive mutant previously isolated in the mammals, gustatory and olfactory information are
Kenyon lab from an unbiased lifespan mutagene- relayed to neurons in the hypothalamus, which
sis screen. We have shown that this mutant affects controls neuroendocrine function, physiology and
behavior. Thus, the sensory systems of other ani-
A B mals might also influence their lifespan.
We have been testing this hypothesis by deter-
mining whether Drosophila sensory mutants also
have lifespan phenotypes. So far, we have found that
flies missing a subset of taste bristles live longer.
These taste bristles are located in the fly labella and
are innervated by gustatory neurons that extend
processes to the subesophageal ganglion (SOG), a
region in the brain that relays sensory information.
Fig. 2. A Certain gustatory For example, the SOG interneurons project axons
neurons inhibit and others the normal development of the sensory cilia, which to or near the insulin-producing cells in the fly
promote longevity. Both are important in the chemotactic responses of the brain. Hence, we are currently testing whether flies
classes appear to modulate worm to environmental stimuli. We have found missing labellar taste bristles have altered insulin
insulin/IGF-1 signaling to
that the temperature-sensitive defect in the sen- expression and exhibit phenotypes other than al-
affect worm lifespan.
B Worm gonad precursor
sory cilia correlates with the temperature-sensitive tered lifespan, e.g., feeding behavior and further
cells. Germline cells (green lifespan phenotype. At the restrictive temperature, phenotypes associated with decreased insulin/
circles) inhibit longevity; the mutant exhibits a defect in its sensory cilia and IGF-1 signaling.
the somatic gonad (blue lives longer than wild-type worms, whereas at the We have also found that flies lacking most of
circles) promotes longevity permissive temperature the mutant exhibits wild- their taste bristles do not live as long as flies lack-
in an olfactory neuron- type sensory cilia and wild-type lifespan. Since the ing only labellar taste bristles. As in C. elegans, it
dependent manner
defect in the sensory cilia of this mutant is rever- is possible that Drosophila has both taste neurons
sible, we have performed temperature-shift exper- that promote and taste neurons that inhibit
iments to determine the temporal requirement for longevity. If this is the case, the activities of these
this gene in the regulation of worm lifespan. We two neuron classes may either antagonize each
found that the product of this sensory gene must other or the activity of the longevity-inhibiting
be present late in larval development in order to neurons may require the activity of the longevity-
influence lifespan. Since specific sensory neurons promoting neurons to influence lifespan. Together
seem to modulate the activities of different signal- our findings suggest that the Drosophila sensory
ing pathways in their effects on lifespan, we are also system, like that of C. elegans, also influences lifes-
determining through laser ablations whether spe- pan and involves both positive and negative sen-
cific neurons also function at different stages of de- sory inputs.
velopment to affect lifespan.
Selected publications
Alcedo J, Kenyon C (2004) Alcedo J, Ayzenzon M, Von Ohlen T, Alcedo J, Zou Y, Noll M (2000)
Regulation of C. elegans longevity by Noll M, Hooper JE (1996) Posttranscriptional regulation of
specific gustatory and olfactory neurons. The Drosophila smoothened gene encodes Smoothened is part of a self-correcting
Neuron 41:45-55 (and Cover) a seven-pass membrane protein, a putative mechanism in the Hedgehog signaling
receptor for the Hedgehog signal. Cell system. Mol Cell 6:457-465
Alcedo J, Noll M (1997) 86:221-232
Hedgehog and its Patched-Smoothened
receptor complex: a novel signalling
mechanism at the cell surface. Biol Chem
378:583-590 (and Cover)
INTRODUCTION
Cells in tissues constantly sense their environment
via cell surface receptors that interact with ligands
on neighboring cells or with molecules of the ex-
tracellular matrix (ECM). These interactions in-
fluence the differentiation status of cells by controll-
ing intracellular signaling pathways that regulate
cellular gene expression programs. Perturbations
in these interactions lead to multiple diseases such GROUP LEADER
as cancer or degenerative diseases. Ruth Chiquet-Ehrismann
For the proper functioning of connective tissues, ruth.chiquet@fmi.ch
the integrity and maintenance of the link between
the ECM of a given tissue with cellular receptors TECHNICAL/RESEARCH
and the cytoskeleton of the cells synthesizing the ASSOCIATES
tissue-specific ECM is essential. This is exempli- Marianne Brown-Ldi
fied by muscle, in which mutations in proteins of Jacqueline Ferralli
the cytoskeleton, transmembrane proteins linking
it to the ECM, or ECM proteins themselves can lead POSTDOCTORAL
to muscular dystrophies, or by skin, in which such FELLOWS
mutations cause blistering diseases. Florence Brellier
In our lab, we focus on several proteins impor- Stefano Canevascini*
tant for connective tissue function. Tenascin-C and Krzysztof Drabikowski*
tenascin-W are present in tendon and bone ECM Laurent Gelman
as well as in the stromal compartment of many Silke Maier
tumors. Therefore, we analyze the anti-adhesive
and tumor growth-promoting functions of the PhD STUDENTS
tenascin family of ECM proteins and attempt Michaela Brosig
to identify their interaction partners and cellular Iwona Bucior*
receptors. Agrin is present in the basal lamina of Martin Degen
muscle as well as at neuromuscular junctions, Ana Hrus
where it regulates the clustering of acetylcholine Daniela Kenzelmann
receptors. We delineate certain aspects of agrin Samantha Nunes*
function in the model organism Caenorhabditis el- Agnieszka Trzebiatowska
egans.
Recently, we discovered a novel cell surface re- UNDERGRADUATES
ceptor family that we termed teneurins. Teneurins Gordon Lau*
are transmembrane proteins with an intracellular Enrico Martina*
domain involved in signal transduction and a large Thomas Walpen*
extracellular part involved in cell-cell interactions.
We analyze teneurin function in vitro by molecu- GUEST SCIENTISTS
lar and cell biological experiments and in vivo us- Matthias Chiquet
ing C. elegans. Bradley Ian Morrison*
Richard Tucker*
C-terminus, termed TCAP (reported by D.A. Love- where it may influence gene expression. Little is
joy), homophilic interaction through the extra- known, however, about the cleavage mechanism
cellular domains distal of the EGF-like repeats and and target genes.
receptor dimerization through cysteine bridges C. elegans has a single teneurin orthologue un-
between the EGF-like repeats two and five. The in- der the control of alternative promoters. The up-
tracellular domain is linked to the cytoskeleton stream promoter is active in the somatic gonad,
through its interaction with the adaptor protein some muscle cells, the gut and a number of neu-
CAP/ponsin. After proteolytic release of the intra- rons. Expression from the downstream promoter
cellular domain, this part of the protein may in- is mainly detected in the nervous system. TEN-1
teract with further nuclear proteins like MBD1 and is a type II transmembrane protein consisting of
zic to influence gene transcription. a short intracellular domain, a transmembrane do-
This type of direct signaling from a cell surface main, and a long, highly conserved extracellular
receptor to the nucleus by regulated intramem- part containing eight EGF-like repeats, a cysteine
rich region and YD repeats.
Ten-1 mutant phenotype
To determine the function of TEN-1 in C. ele-
gans, we investigated the two loss-of-function mu-
tants ten-1(ok641) and ten-1(tm651). The former
carries an in-frame deletion of four EGF-like re-
peats and part of the cysteine rich region. The lat-
ter has a deletion that removes the transmembrane
domain and introduces a frameshift mutation, re-
sulting in the loss of all but the first few amino acids
of the protein. In both mutants, transcripts for the
predicted truncated proteins were detected at a
Fig.3. Left: Penetrance of level comparable to the wild-type form. Both ten-1
the phenotypes of Ten-1 branous proteolysis has been found for many re- mutants show a pleiotropic phenotype similar to
mutant worms. Right: The ceptor proteins and has probably been most thor- that observed after reduction of ten-1 expression
well-organized gonad of oughly analyzed in the case of Notch signaling. The by RNAi. Mutant worms are sterile due to various
a wild-type compared
proposed mechanism of action of teneurins by defects in the somatic gonad and ectopic germline
with a Ten-1 mutant worm
cleavage of the intracellular domain and its trans- formation in the proximity of the vulva (Fig. 3).
location to the nucleus needs to be studied more Time-course analysis of germline development
rigorously. The cleavage site and the protease(s) showed that these abnormalities may result from
must be identified and the function of the intra- an early defect in somatic gonad formation. We
cellular domain within the nucleus elucidated. partially rescued the phenotype of ten-1(ok641)
mutant worms by injecting cosmid F36A3 carry-
TEN-1 IS REQUIRED FOR THE FORMATION OF ing the entire genomic region of the ten-1 gene.
THE SOMATIC GONAD Since such an extrachromosomal array is likely to
be silenced in the germline, gonadal defects appear
K. Drabikowski, A. Trzebiatowska
to be the result of impaired signaling in the somatic
C. elegans TEN-1, also a member of the teneurin gonad.
family, was proposed to act as a receptor that sig-
nals directly to the nucleus. Its intracellular do-
main is cleaved and translocates to the nucleus
Selected publications
Drabikowski K, Trzebiatowska A, Nunes-Radimerski S, Ferralli J, Choi KD, Scherberich A, Tucker RP, Degen M,
Chiquet-Ehrismann R (2005) Minet A, Chiquet-Ehrismann R (2005) Brown-Luedi M, Andrs AC,
ten-1, an essential gene for germ cell devel- The intracellular domain of teneurin-1 Chiquet-Ehrismann R (2005)
opment, epidermal morphogenesis, gonad interacts with MBD1 and CAP/ponsin Tenascin-W is found in malignant mammary
migration, and neuronal pathfinding in Cae- resulting in subcellular co-distribution tumors, promotes alpha8 integrin-depen-
norhabditis elegans. Dev Biol 282:27-38 and translocation to the nuclear matrix. dent motility and requires p38MAPK activ-
Exp Cell Res 305:122-132 ity for BMP-2 and TNF-alpha induced ex-
pression in vitro. Oncogene 24:1525-1532
Ruiz C, Huang W, Hegi ME, Lange K,
Hamou M-F, Fluri E, Oakeley EJ, Tucker RP, Chiquet-Ehrismann R (2006)
Chiquet-Ehrismann R, Orend G (2004) Teneurins: a conserved family of transmem-
Differential gene expression analysis reveals brane proteins involved in intercellular
activation of Wnt and MAPK signaling and signaling during development. Dev Biol
downregulation of tropomyosin-1 by 290:237-245
tenascin-C. Cancer Res 64:7377-7385
INTRODUCTION
The molecular tapestries of signal transduction
pathways in living organisms from humble yeast
to the rather less humble human brain are being
revealed as complex networks. This revelation is
driven in part by the genomics revolution. Genomes
are being sequenced, open reading frames hunted
down and new signal connections elucidated. It is
now possible to identify in principle all signalling GROUP LEADER
components elaborated by any particular cell. Clas- Brian A. Hemmings
sical signalling pathways are triggered by binding of brian.hemmings@fmi.ch
an extracellular ligand (growth factors, cytokines,
chemokines, hormones, neurotransmitters) to the TECHNICAL/RESEARCH
appropriate plasma membrane receptor. In nor- ASSOCIATES
mal physiology, these signalling pathways interact Peter David Cron
in complex networks to invoke appropriate cellular Deborah Hynx
responses. This involves often subtle and reversible
alterations of multiple protein functions, such as POSTDOCTORAL
intrinsic activity, subcellular localization, half-life, FELLOWS
or interaction of proteins with binding partners. Anne Baudry*
The most common mechanism is phosphorylation Elisabeth Fayard
performed by protein kinases, the largest family of Ekaterina Gresko
enzymes in the human genome. Over 500 different Alexander Hergovich
enzymes can phosphorylate one-third of all intra- Pier Morin
cellular proteins, making kinases the key regula- Arnaud Parcellier
tors in signalling. Accordingly, temporal and spatial Jongsun Park*
regulation of protein kinases is of great importance Lionel Tintignac
in controlling all aspects of cell biology: metabo- Anton Vichalkovski
lism, transcription, cell growth, shape, migration, Zhongzhou Yang*
survival and differentiation.
Our work focuses on the physiological role and PhD STUDENTS
regulation of kinases in eukaryotic signalling path- Samuel Bichsel*
ways, especially their involvement in human dis- Lana Bozulic
ease. Many diseases arise by deregulation of signal Hauke Cornils
transduction pathways leading to inappropriate Bettina Dmmler
signalling. In cancer cells, mutations in key regu- Daniel Heisswolf*
latory enzymes result in permanently up-regulated David Restuccia
proliferation and survival signalling pathways. De- Debora Schmitz
ciphering the processes controlling protein kinase Mario Stegert*
activity will allow development of therapeutics tar- Banu Src
geting specific pathways to alleviate human disease. Oliver Tschopp*
Monika Wnuk*
UNDERGRADUATES
Reto Kohler
Magdalena Paolino*
Fig. 2. NDR kinase family Earlier results underline the importance of NDR
signalling. A LATS1/2 acti- IDENTIFICATION OF MST3 AS AN HYDROPHOBIC kinase family members for higher organisms.
vated by MST1/2 in turn MOTIF KINASE OF NDR However, the specific physiological role of mam-
inactivates YAP. RAF1 is a malian NDR kinases is still unknown.We are work-
positive, RASSF1/NORE1 M. Stegert, A. Hergovich, A. Vichalkovsky
ing on mouse models for NDR1- and NDR2 defi-
a negative regulator of
MST1/2. MOB1 directly
Human NDR1/2 and LATS1/2 are also activated by ciency to investigate the function of these kinases
interacts with LATS1/2 as phosphorylation through mammalian Ste20-like in a mammalian system. Mice deficient for NDR1
a co-activator. B NDR1/2 (MST) kinases. MST1/2 phosphorylates LATS1/2 are fertile and display no developmental defects.
is activated by MST3 with in vitro, while MST3 targets NDR1/2. We have However, aged NDR1 knock-out mice develop tu-
MOB1/2 serving as co- established that MST3 phosphorylates human mours at a higher frequency than wild-type litter
activator. hFurry may serve NDR1/2 at the membrane. MST3 targets the hy- mates.
as scaffold protein in this
drophobic motif phosphorylation site of NDR1/2 In parallel,the murine NDR2 locus is being condi-
activation. Bold lines vali-
dated interactions, dotted
but not the activation segment phosphorylation tionally targeted. This will allow us to abolish NDR2
lines putative, question site. Biochemical studies resulted in the following in a time-point- and tissue-specific manner to study
marks unknown upstream model for NDR regulation: hMOBs bind to the the role of NDR2 at defined developmental stages
regulators, substrates or NTR of human NDR1/2 and promote release of and in distinct tissues. As the expression patterns
direct interaction partners the auto-inhibition of the activation segment lead- of NDR1 and 2 overlap, mice lacking NDR1 and 2
ing to auto-phosphorylation (Ser281 of human will be generated by crossing the single knock-out
NDR1). hMOBs are recruited to the plasma mem- animals to exclude mutual compensation by either
brane by an unknown mechanism,bringing NDR1/2 isoform. Our genetic studies should provide insights
into close proximity to its upstream activators; into the in vivo roles of these protein kinases.
MST3 phosphorylates NDR1/2 on the hydropho-
bic motif (Thr444 of human NDR1) resulting in a
fully active NDR kinase.Thus, binding of MOBs to
the N-terminus of NDR elevates auto-phosphory-
Selected publications
Baudry A, Yang ZZ, Hemmings BA (2006) Hergovich A, Stegert MR, Schmitz D, Tschopp O, Yang ZZ, Brodbeck D,
PKBa is required for adipose differentiation Hemmings BA (2006) Dummler BA, Hemmings-Mieszczak M,
of mouse embryonic fibroblasts. J Cell Sci NDR kinases regulate essential cell Watanabe T, Michaelis T, Frahm J,
119:889-897 processes from yeast to humans. Nature Hemmings BA (2005)
Rev Mol Cell Biol 7:253-264 Essential role of protein kinase B g
Hergovich A, Bichsel SJ, Hemmings BA (PKBg/Akt3) in postnatal brain develop-
(2005) Stegert MR, Hergovich A, Tamaskovic R, ment but not in glucose homeostasis.
Human NDR kinases are rapidly activated Bichsel SJ, Hemmings BA (2005) Development 132:2943-2954
by MOB proteins through recruitment to Regulation of NDR protein kinase by hy-
the plasma membrane and phosphorylation. drophobic motif phosphorylation mediated
Mol Cell Biol 25:8259-8272 by the mammalian Ste20-like kinase
MST3. Mol Cell Biol 25:11019-11029
INTRODUCTION
Covalent modification of amino acids greatly ex-
tends the repertoire of chemical and, thus, func-
tional properties of proteins. We focus on two
forms of glycosylation and on tyrosine phospho-
rylation of ErbB2, a receptor tyrosine kinase.
Glycosylation is crucial for the development,
growth and survival of an organism. However,
defining the exact function and/or mechanism of GROUP LEADER
action of glycan modifications at the molecular Jan Hofsteenge
level remains a major challenge in glycobiology. The jan.hofsteenge@fmi.ch
importance of glycosylation is shown by the num-
ber of diseases, e.g. neurological disorders, mus- TECHNICAL/RESEARCH
cular dystrophies or lysosomal storage diseases, ASSOCIATES
now known to be due to defects in glycosyltrans- Marianne Grob*
ferases, sugar-transporters, glycosidases or lectins. Dominique Klein
Furthermore, knocking out core glycosyltransfer-
ases nearly always results in a severe, if not lethal, POSTDOCTORAL
phenotype. This is complemented by the discov- FELLOWS
ery of many lectins involved in cellular and phys- Stefano Canevascini
iological processes, e.g. quality control of protein Guillaume De Sampaio*
folding and leukocyte homing. Thus, we begin to Jeremy Keusch
see the enormous coding potential of carbohy-
drates. PhD STUDENTS
We aim to define the biological function of Constanze Heinrich
C-mannosyltryptophan and glucosyl-fucosyl-O- Krisztina Kozma
Ser/Thr (Fig. 1). Both modifications occur close Carsten Krantz
together in thrombospondin type 1 repeats (TSRs). Florence Roux
This module is an essential domain in a range of
proteins with roles in normal physiologyas well as UNDERGRADUATES
in disease, e.g. in the invasion of vector and host Jasmin Althaus*
cells by protozoan parasites. Nominerdene Battsengel*
ErbB2 is one of four tyrosine kinases closely Alexandra Bezler*
related to the EGF receptor and frequently overex- Pascal Hermann*
pressed in cancers. Growth factor binding to het-
erodimers formed with other members of the fam-
ily leads to phosphorylation of tyrosine residues *left the group
in its intracellular domain. These serve as docking
sites for proteins that initiate intracellular signal-
ling pathways. We are studying the temporal dy-
namics of signalling events following growth fac-
tor stimulation and the importance of individual
phosphorylated tyrosine residues for tumor for-
mation.
Part of the group runs the protein- and peptide
analysis facility.
MODIFICATION OF THROMBOSPONDIN TYPE 1 cell (DTC). A major cue for the ventral to dorsal
REPEATS WITH Glc-Fuc-O- migration of the DTCs results from the repulsive
signal created by ventrally expressed netrin (UNC-
S. Canevascini, K. Kozma, M. Grob, J. Althaus,
6) that is sensed by two receptors in the DTC,
D. Klein and J. Hofsteenge, in collaboration with
UNC-5 and UNC-40. The former contains TSRs,
R. Chiquet-Ehrismann (FMI)
one of which could be O-fucosylated. Interestingly,
Previously, we found that TSRs in mammalian pro- the phenotype of pad-2(tm1756) is very similar
teins can be modified by addition of the di-sac- to that published for the precocious expression
charide Glc-Fuc-O-. Our current research in this of UNC-5. Our recent genetic experiments have
area aims at finding the biological function of this shown that the unc-6, unc-5 and unc-40 genes
form of glycosylation using C. elegans as a model are epistatic to pad-2. We are currently testing the
system. Before starting genetic analyses, it was nec- hypothesis that pad-2 acts as an inhibitor of the
essary to perform biochemical studies to ascertain netrin pathway in the DTC.
that the modification occurs in C. elegans and Obviously, deletion of the enzymatic activity of
to identify the two glycosyltransferases involved. POFUT-2 results in the absence of the entire Glc-
We have established an in vitro assay for the de- Fuc-O- disaccharide. To examine the role of the
termination of TSR-O-fucosyltransferase activity missing glucosyl residue in the pad-2(tm1756)
in extracts from cells and entire worms. Using this phenotype, it will be of interest to study the effect
assay with cells overexpressing putative O-fucosyl- of mutating the activity of b1,3-GlcT.
transferases from C.elegans, we demonstrated that
the pad-2 gene encodes the fucosyltransferase (PO- PROTEIN C-MANNOSYLATION
FUT-2) that modifies TSRs. Importantly, product
J. Keusch, C. Krantz and D. Klein, in collaboration
analysis of isolated peptides by mass spectrometry
with E. Jacoby and P. Frst (NIBR, Basel)
showed that the enzyme attaches the fucosyl
residue in the correct position within the TSR. We are following two approaches to the function
of protein C-mannosylation. First, we are search-
ing for ways to alter the activity of the protein
C-mannosyltransferase (PCMT) in cells and model
organisms, preferably C. elegans. In order to ge-
netically manipulate PCMT activity, we wish to
identify its gene by an expression cloning approach.
Since no suitable cell lines could be found for
this task, we mutagenized an engineered CHO cell
line carrying a C-mannosylation reporter on its
C-a
a-mannosyltryptophan glucosyl-fucosyl-O-Serine
plasma membrane. We obtained several lines lack-
Fig.1. Molecular structure ing C-mannosylation that are otherwise normal
of the C- and O-linked glyco- The fucose residue in TSRs can be extended by with respect to the level of C-mannosylation re-
conjugates studied in this the action of an as yet unidentified glucosyltrans- porter and the synthesis of the sugar donor
report. The position of ferase (b1,3-GlcT) by the addition of a glucosyl dolichylphosphomannose (MPD). In an alterna-
the C -atom of the amino residue. We have found that C. elegans possesses tive approach, we are looking for chemicals that
acid has been indicated
this enzyme activity. Using the recombinant PO- inhibit PCMT. Our collaborators have performed
with a red dot
FUT2 preparations described above, we produced in silico searches on the NIBR small compound li-
sufficient quantities of pure TSR-fucose to estab- braries and identified molecules that might fit the
lish an assay for b1,3-GlcT. Using enzymatic assays active site of PCMT. Using the engineered CHO
and product analysis by mass spectrometry to ex- cell line, we identified 12 compounds that strongly
amine candidate genes in a way very similar to that reduce modification of the C-mannosylation and
described for POFUT-2, we have now identified are, thus, putative PCMT inhibitors. Interestingly,
the human gene encoding b1,3-GlcT. the results of further characterization of these
In collaboration with Dr.S.Mitani (NBRP,Japan), compounds, together with observations made in
we obtained a C. elegans mutant, pad-2(tm1756), mutant CHO lines aberrant in MPD synthesis,
that contains a large deletion in the 5 two-thirds point to the existence of multiple C-mannosylation
of the gene. The tm1756 strain is homozygous vi- pathways, one of which appears to be independent
able and lacks all fucosyltransferase activity to- of MDP.
wards a TSR. We observed that the ventral part of The second approach to study the function of
the anterior gonad arm in mutant worms leaves the protein C-mannosylation is based on our obser-
muscle band prematurely, running with an oblique vation that the patterns of C-mannosylation and
angle towards the dorsal muscle band (Fig. 2). O-fucosylation on the surface of TSRs differ be-
Abnormal gonad shape is generally considered tween proteins. This suggests the existence of a
to result from defects in guidance of the distal tip sugar code that specifies protein-protein inter-
ErbB2 PHOSPHORYLATION
F. Roux and C. Heinrich, in collaboration with
N. Hynes (FMI)
Selected publications
Furmanek A, Hess D, Rogniaux H, Mormann M, Macek B, Gonzalez de Peredo A, Zanetta J-P, Pon A, Richet C, Timmerman P,
Hofsteenge J (2003) Hofsteenge J, Peter-Katalinic J (2004) Leroy Y, Bohin J-P, Trinel P-A, Poulain D,
The WSAWS motif is C-hexosylated in a Structural studies on protein O-fucosylation Hofsteenge J (2004)
soluble form of the erythropoietin receptor. by electron capture dissociation. Int J Mass Quantitative determination of C-mannosyla-
Biochemistry 42:8452-8458 Spectrom 234:11-21 tion of tryptophan residues in glycoproteins.
Anal Biochem 329:199-206
Nancy Hynes
The molecular basis
of breast cancer
INTRODUCTION
Cancer results from cumulative alterations in the
genetic make-up of somatic cells that lead to aber-
rant expression, mutation or deletion of proteins
modulating cellular proliferation, differentiation
and survival. Through deregulation of intracellu-
lar pathways, these defects allow cancer cells to
evade signals that normally tightly control cell pro-
liferation and survival. Cancer cells also signal GROUP LEADER
abnormally to their surroundings. One important Nancy Hynes
outcome is the stimulation of neovascular growth, nancy.hynes@fmi.ch
which provides nourishment for the tumor and
promotes metastasis. Receptor tyrosine kinases TECHNICAL/RESEARCH
(RTKs) are often aberrantly activated in human ASSOCIATES
cancers, which impacts on multiple characteristics Susanne Lienhard
of the cancer phenotype. Constitutive activation Francisca Maurer
of the ERBB family is often found in breast cancer,
including epidermal growth factor receptor (EGFR) POSTDOCTORAL
and ERBB2 as well as members of the fibroblast FELLOWS
growth factor receptor (FGFR) family. We are Ali Badache*
studying the intracellular signaling pathways acti- Anne Boulay
vated by these receptors. Targeted approaches are David Cappellen*
used to inactive the receptors and their effects on Subha Susan Jacob*
cancer cell proliferation, survival, migration and Rgis Masson
other characteristics are determined. We also study Thomas Schlange
cross-talk between signaling molecules in cancer Patrizia Sini
cells. ERBB receptors are important mediators of
signaling from other classes of membrane recep- PhD STUDENTS
tors, for example the Wnt/Fz network, which po- Ilja Boschke*
tentially has a role in autocrine ERBB receptor and Julien Dey
downstream signaling pathway activation. Barbara Hnzi
A major goal of our research is to go from a de- Patrick Kaeser
scription of the molecular alterations in breast can- Na Li*
cer cells to an understanding of how these altered Yutaka Matsuda
signal transduction proteins contribute to the meta- Maria Meira
static cancer process. A greater understanding of Ivana Samarzija
the molecular basis of cancer will be essential for Tina Stlzle
the rational development and clinical application
of the new classes of targeted signal transduction UNDERGRADUATES
inhibitors now being used for cancer therapy. Collin Ewald
Sven Falk*
Alexandre Huber*
tributing to this process. Using ERBB2-dependent using a Memo-specific shRNA vector. Initial results
tumor cell migration as a model,we have shown that suggest that the metastatic spread from primary
two of the autophosphorylated tyrosine residues in tumors to the lungs is impaired in tumor cells with
ERBB2s cytoplasmic domain (Tyr 1201 and 1227) decreased levels of Memo.
support long-term migration. We used phospho-
peptides corresponding to these receptor regions CROSS-TALK BETWEEN THE Wnt PATHWAY AND
as affinity reagents and identified proteins from ERBB RECEPTORS IN BREAST CANCER
tumor cell extracts that bound specifically to the
T. Schlange, D. Cappellen, Y. Matsuda,
phospho-peptides. Several proteins were identified
S. Falk, A. Huber
(Fig. 2A) including Shc, PLC g and Crk isoforms
that bind Y1201, and the Y1227 binders Shc and Wnts are secreted glycoproteins that play impor-
Memo (mediator of ERB2-driven-cell motility). tant roles in normal development. Members of the
Although siRNA-mediated knock-down of each Frizzled (Fz) family of transmembrane proteins
protein impairs ERBB2-induced cell motility, ana- are receptors for Wnts. Wnt binding to Fz initiates
lysis of actin and microtubule networks in migrat- a pathway that prevents GSK-3 b from phosphory-
ing cells has revealed interesting differences. Shc lating b-catenin, leading to its stabilization and
knock-down cells fail to extend actin-based lamel- translocation to the nucleus, where it engages tran-
lipodia in response to ERBB2 activation, while scription factors of the TCF family. This pathway
Memo knock-down cells form lamellipodia but fail drives the development of many human cancers.
Unlike colon cancer, in which activating pathway
A The ErbB2 receptor B E13.5 mutations are often found, breast tumors show lit-
tle evidence of such mutations; however, emerging
evidence suggests that Wnt/Fz signaling is active due,
for example, to loss of expression of the negative
regulator sFRP.We are exploring the role of Wnt/Fz
pathway activation in breast cancer. Our results
suggest that in addition to the canonical pathway
leading to b-catenin stabilization and TCF activ-
ity, Wnts have a role in ERBB receptor activation.
Activation of the ERBB receptors is controlled
by the spatial and temporal expression of their lig-
ands, members of the EGF-family, which are pro-
duced as transmembrane precursors and cleaved by
cell surface proteases, a step that leads to release of
Memo antisense probe
soluble ligands. This cleavage, termed ectodomain
Fig. 2. A Activation of shedding, is an important step in the control of lig-
ERBB2 leads to phosphory- to extend the microtubule network to the cell cor- and availability and receptor activation. ERBB re-
lation of tyrosine residues tex. These results suggest that signaling pathways ceptors are constitutively stimulated in many pri-
in its cytoplasmic domain. triggered by specific phospho-tyrosine residues in mary tumors since EGF family ligands are often
Two residues (Y1201,
ERBB2 cooperate at different levels to induce tu- co-expressed in the tumor. Thus, it is essential to
Y1227) support tumor cell
migration by binding the
mor cell migration. understand the mechanisms that control ligand
indicated signaling proteins. Memo is a novel protein with an as yet unknown processing.
Memo is a novel P-Y1227- function. A bioinformatic analysis revealed that The proteases involved in ectodomain shedding
interacting protein. B In situ Memo homologs are present in all branches of life. are metalloproteinases. The production of soluble
hybridization with a Memo Memo is expressed in most adult tissues and dur- EGF family ligands occurs in response to diverse
antisense cRNA probe on an ing embryonic development. Figure 2B shows the stimuli and was first described following activa-
E13.5 mouse embryo sagit-
results of in situ hybridization with a Memo anti- tion of G protein-coupled receptors (GPCR). In
tal section
sense cRNA probe, carried out on sections of an cells treated with GPCR receptor agonists, metal-
E13.5 mouse embryo. Most embryonic tissues stain loproteinases that induce cleavage and release of
positively, with some showing more expression than EGF ligands are stimulated, leading to the rapid
others. To explore the physiological role of Memo, phosphorylation of EGFR. This process, termed
conventional and conditional Memo knock-out EGFR transactivation, has important biological
mice strains have been generated. implications since it leads to stimulation of intra-
Considering the importance of Memo in tumor cellular pathways such as MAPK/ERK signaling. We
cell migration, we are exploring its role in tumor have shown that ERBB transactivation also results
cell metastasis using mammary tumor cells that from the binding of Wnt to Fz (Fig. 3). The mech-
rapidly form primary tumors and lung metastases anism appears to be similar to that described for
following injection into the mammary fat pad. Sta- GPCRs, since it is rapid and blocked by metallo-
ble knock-down of Memo expression was achieved proteinase inhibitors. Wnt/Fz-mediated transacti-
Selected publications
Hynes NE, Lane H (2005) Li N, Zhang Y, Naylor MJ, Schatzmann F, Sini P, Wyder L, Schnell C, O'Reilly T,
ERBB receptors and cancer: the complexity Maurer F, Wintermantel T, Schuetz G, Littlewood A, Brandt R, Hynes NE, Wood J
of targeted inhibitors. Nature Rev Cancer Mueller U, Streuli CH, Hynes NE (2005) (2005)
5:341-354 b1 integrins regulate mammary gland pro- The antitumor and antiangiogenic activity
liferation and maintain the integrity of of vascular endothelial growth factor re-
Koziczak M, Hynes NE (2004) mammary alveoli. EMBO J 24:1942-1953 ceptor inhibition is potentiated by ErbB1
Cooperation between FGFR-4 and ErbB2 blockade. Clin Cancer Res 11:4521-4532
in regulation of cyclin D1 translation. Marone R, Hess D, Dankort D, Muller WJ,
J Biol Chem 279:50004-50011 Hynes NE, Badache A (2004)
Memo mediates ErbB2-driven cell motility.
Nature Cell Biol 6:515-522
Yoshikuni Nagamine
Regulation of the
plasminogen activator
system with emphasis on
the DExH helicase RHAU
INTRODUCTION
The stability of mRNA is one of the important reg-
ulatory steps determining the global level of gene
expression. mRNA stability is regulated via inter-
actions between cis-acting elements in the mRNA
and trans-acting factors recognizing these elements.
Of the cis elements identified so far, the most wide-
spread and studied is the AU-rich element (ARE),
a stretch of 50-100 nt located upstream of the GROUP LEADER
poly(A) signal in the 3untranslated region (3UTR) Yoshikuni Nagamine
that confers instability and is present at any one yoshikuni.nagamine@fmi.ch
time in about 8 % of total mRNAs. The ARE are
classified into at least three groups according to TECHNICAL/RESEARCH
the number and arrangement of a conserved pen- ASSOCIATES
tanucleotide motif AUUA. Various trans factors Sandra Pauli
have been identified that recognize ARE. During Stphane Thiry
the study of the ARE of urokinase-type plasmino-
gen activator mRNA (uPA), the expression level of POSTDOCTORAL
which is high in many metastatic tumors and in- FELLOWS
flammatory cells, we identified a novel DExH RNA Nobuyoshi Akimitsu*
helicase that enhances poly (A) tail shortening and Nives Selak
mRNA decay.
Numerous RNA helicases in a large DExH/D su- PhD STUDENTS
perfamily are engaged in almost all aspects of RNA Katerina Chalupnikova
metabolism from transcription, mRNA splicing, Fumiko Iwamoto
rRNA maturation, nuclear transport, and mRNA Sandra Kleiner*
translation to mRNA stability. Mutation studies in Ching Janice Lai
yeast indicate that each RNA helicase has a specific Simon Lattmann
function and plays an essential role in the cell. Svetlana Shustova
These enzymes contain a helicase core domain Joshi Venugopal*
of 350-400 amino acids consisting of 8-9 highly
conserved sequence motifs flanked by much less UNDERGRADUATES
conserved N- and C-terminal regions of variable Lauren Smith*
lengths. Not all DExH helicases have been shown Morteza Yazdani Shektaei*
to possess double-stranded RNA unwinding activ-
ity. Rather, they appear to exert biological activi- *left the group
ties through modulating protein-RNA interaction.
Mammals express more DExH/D helicases than
yeast and worms, but the functions and regulation
of most of them are as yet unknown. There is
no RHAU homologue in yeasts or Caenorhabditis
elegans.
Selected publications
Nagamine Y, Muoz-Cnoves P, Medcalf RL Vaughn JP, Creacy SD, Routh ED, Venugopal J, Hanashiro K, Yang ZZ,
(2005) Joyner-Butt C, Jenkins GS, Pauli S, Nagamine Y (2004)
Transcriptional and posttranscriptional Nagamine Y, Akman SA (2005) Identification and modulation of a caveo-
regulation of the plasminogen activator sys- The DEXH protein product of the DHX36 lae-dependent signal pathway that regu-
tem. Thromb Haemost 93:661-675 gene is the major source of tetramolecular lates plasminogen activator inhibitor-1
quadruplex G4-DNA resolving activity in in insulin-resistant adipocytes. Proc Nat
HeLa cell lysates. J Biol Chem 280:38117- Acad Sci USA 101:17120-17125
38120
Human resources
Rudi Unrau
Susan Thomas
Marilyn Vaccaro
Informatics
Dean Flanders
Alessandro Di Cara*
Brett Ellis*
Leandro Hermida
James Melendez*
Alan Naylor
Thomas Nyffenegger
Ingeborg Obergfll
Thibaut Siegmann
Sjoerd Van Eeden
Novartis Institutes
for Biomedical Research
Andreas Lthi Collaboration with the
George Thomas
University of Basel
Oncosuisse Collaborative Cancer
Research Projects We are very grateful to the University
Brian Hemmings of Basel, in particular the faculty
Nancy Hynes of the Biozentrum, for their continued
cooperation in research and in our
Roche Research Foundation International PhD Programme.
Brian Hemmings
Andreas Lthi
Richards DA, Mateos JM, Hugel S, Ruiz C, Huang W, Hegi ME, Lange K, Haase A, Jaskiewicz L, Zhang H, Lain S,
de Paola V, Caroni P, Gahwiler BH, Hamou M-F, Fluri E, Oakeley EJ, Sack R, Gatignol A, Filipowicz W (2005)
McKinney RA (2005) Chiquet-Ehrismann R, Orend G (2004) TRBP, a regulator of cellular PKR
Glutamate induces the rapid formation Differential gene expression analysis and HIV-1 virus expression, interacts with
of spine head protrusions in hippocampal reveals activation of Wnt and MAPK Dicer and functions in RNA silencing.
slice cultures. Proc Natl Acad Sci USA signaling and downregulation of EMBO Rep 6:961-967
102:6166-6171 tropomyosin-1 by tenascin-C. Cancer
Res 64:7377-7385 Kolb FA, Zhang H, Jaronczyk K, Tahbaz N,
Willmann R, Pun S, Stallmach L, Hobman TC, Filipowicz W (2005)
Sadavisam G, Santos AF, Caroni P, Scherberich A, Tucker RP, Human Dicer: purification, properties
Fuhrer C (2006) Degen M, Brown-Luedi M, Andrs AC, and interaction with PAZ PIWI domain
Cholesterol and lipid microdomains Chiquet-Ehrismann R (2005) proteins. Meth Enzymol 392:316-336
stabilize the postsynapse at the neuro- Tenascin-W is found in malignant
muscular junction. EMBO J (in press) mammary tumors, promotes alpha8 in- Kotaja N, Bhattacharyya S, Jaskiewicz L,
tegrin-dependent motility and requires Kimmins S, Parvinen M, Filipowicz W,
p38 MAPK activity for BMP-2 and Sassone-Corsi P (2006)
Group Ruth Chiquet-Ehrismann TNF-alpha induced expression in vitro. The chromatoid body of male germ cells:
Oncogene 24:1525-1532 similarity with P-bodies and presence
Baumann P, Soric N, Kroese F, Orend G, of Dicer and microRNA pathway compo-
Chiquet-Ehrismann R, Uede T, Yagita H, Tucker RP, Chiquet-Ehrismann R (2006) nents. Proc Natl Acad Sci USA
Sleeman P (2005) Teneurins: a conserved family of trans- 103:2647-2552
CD24 expression causes acquisition membrane proteins involved in inter- Pellino J, Jaskiewicz L, Filipowicz W,
of multiple cellular properties associated cellular signaling during development. Sontheimer EJ (2005)
with tumor growth and metastasis. Dev Biol 290:237-245 ATP modulates siRNA interactions with
Cancer Res 65:10783-10793 an endogenous human Dicer complex.
Tucker RP, Drabikowski K, Hess J, RNA 11:1719-1724
Canevascini S (2004) Chiquet-Ehrismann R, Adams JC (2006)
Genetic analysis of vulva development in Phylogenetic analysis of the tenascin gene Pillai R (2005)
C. elegans. In: Beffa M, Knight J (eds) family: evidence of origin early in the MicroRNA function: multiple mechanisms
Key techniques in practical developmen- chordate lineage. BMC Evol Biol (in press) for a tiny RNA? RNA 11:1753-1761
tal biology. Cambridge University Press,
New York, pp 153-166 Veit G, Hansen U, Keene DR, Bruckner P, Pillai R, Artus C, Filipowicz W (2004)
Chiquet-Ehrismann R, Chiquet M, Tethering of human Ago proteins
Drabikowski K, Trzebiatowska A, Koch M (2006) to mRNA mimics the miRNA-mediated
Chiquet-Ehrismann R (2005) Collagen XII interacts with avian repression of protein synthesis. RNA
ten-1, an essential gene for germ cell tenascin-X through its NC3 domain. 10:1518-1525
development, epidermal morphogenesis, J Biol Chem (in press)
gonad migration, and neuronal path- Pillai R, Bhattacharyya S, Artus C,
finding in Caenorhabditis elegans. Dev Zoller T, Cougot N, Basyuk E, Bertrand E,
Biol 282:27-38 Group Witold Filipowicz Filipowicz W (2005)
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Isler SG, Ludwig CU, Bhattacharyya SN, Habermacher R, let-7 microRNA in human cells. Science
Chiquet-Ehrismann R, Schenk S (2004) Martine U, Closs EI, Filipowicz W (2006) 309:1573-1576
Evidence for transcriptional repression Stress induced reversal of miRNA repres-
of SPARC-like 1 (SPARCL1), a gene sion and mRNA P-body localization in Putics , Filipowicz W,
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Spring Harbor Laboratory Press (in press) a conserved coronavirus enzyme that is
dispensible for viral replication in tissue
Bhattacharyya S, Habermacher R, culture. J Virol 79:12721-12731
Martine U, Closs EI, Filipowicz W (2006)
Relief of microRNA-mediated trans-
lational repression in human cells sub-
jected to stress. Cell 125:1111-1124
Dummler BA, Hemmings BA (2005) Lechward K, Sugajska E, de Baere I, Group Jan Hofsteenge
Vom Labor zum Krankenbett: Wie Goris J, Hemmings BA, Zolnierowicz S
die Grundlagenforschung zur Entwicklung (2006) Doucey MA, Bender FC, Hess D,
neuer krebsmedikamente fuert. Krebs- Interaction of nucleoredoxin with Hofsteenge J, Bron C (2006)
forschung in der Schweiz. Oncosuisse, protein phosphatase 2A. Febs Lett Caveolin-1 interacts with the chaperone
Krebsliga Schweiz und Krebsforschung 580:3631-3637 complex TCP-1 and modulates its
Schweiz, pp 46-55 protein folding activity. Cell Mol Life Sci
Nagoshi T, Matsui T, Aoyama T, Leri A, 63:939-948
Dummler B, Tschopp OH, Hynx D, Yang ZZ, Anversa P, Li L, Ogawa W, del Monte F,
Dirnhofer S, Hemmings BA (2006) Gwathmey JK, Grazette L, Hemmings BA, El-Shemerly M, Janscak P, Hess D,
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normally developed but display severely PI3K rescues the detrimental effects of 1b upon DNA synthesis inhibition.
affected glucose homeostasis and growth chronic Akt activation in the heart during Cancer Res 65:3604-3609
deficiencies. Mol Cell Biol (in press) ischemia/reperfusion injury. J Clin Invest
115:2128-2138 Ferrari S, Marin O, Pagano MA, Meggio F,
Fayard E, Tintignac LA, Baudry A, Hess D, El-Shemerly M, Krystyniak A,
Hemmings BA (2005) Schmidlin M, Lu M, Leuenberger SA, Pinna LA (2005)
Protein kinase B/Akt at a glance. J Cell Stoecklin G, Mallaun M, Gross B, Aurora-A site specificity: a study with
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Feng J, Park J, Cron P, Hess D, The ARE-dependent RNA destabilizing
Hemmings BA (2004) activity of BRF1 is regulated by protein Haase AD, Jaskiewicz L, Zhang H,
Identification of a PKB/Akt hydro- kinase B. EMBO J 23:4760-4769 Lain S, Sack R, Gatignol A, Filipowicz W
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DNA-dependent protein kinase. J Biol Stegert MR, Hergovich A, Tamaskovic R, TRBP, a regulator of cellular PKR
Chem 279:41189-41196 Bichsel SJ, Hemmings BA (2005) and HIV-1 virus expression, interacts with
Regulation of NDR protein kinase by Dicer and functions in RNA silencing.
Hansen L, Gaster M, Oakeley EJ, hydrophobic motif phosphorylation medi- EMBO Reports 6:961-967
Brusgaard K, Damsgaard Nielsen EM, ated by the mammalian Ste20-like kinase
Beck-Nielsen H, Pedersen O, MST3. Mol Cell Biol 25:11019-11029 Irmler S, Rogniaux H, Hess D,
Hemmings BA (2004) Pillonel Ch (2005)
Expression profiling of insulin action Tan Q, Brusgaard K, Kruse TA, Induction of OS-2 phosphorylation
in human myotubes: induction of inflam- Oakeley E, Hemmings BA, Beck-Nielsen H, in Neurospora crassa by treatment with
matory and proangiogenic pathways Hansen L, Gaster M (2004) phenylpyrrole fungicides and osmotic
in relationship with glycogen synthesis Correspondence analysis of microarray stress. Pestic Biochem Phys 84:25-37
and type 2 diabetes. Biochem Biophys time course data in case-control design.
Res Comm 323:685-695 J Biomed Inform 37:358-365 Schmidlin M, Lu M, Leuenberger SA,
Stoecklin G, Mallaun M, Gross B,
Hemmings BA, Parker PJ (eds) (2005a) Tschopp O, Yang ZZ, Brodbeck D, Gherzi R, Hess D, Hemmings BA,
Cell regulation. Curr Opin Cell Biol Dummler BA, Hemmings-Mieszczak M, Moroni C (2004)
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Hemmings BA (2005) activity of BRF1 is regulated by protein
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Opin Cell Biol 17:105-106 ment but not in glucose homeostasis. Yart A, Gstaiger M, Wirbelauer C,
Development 132:2943-2954 Pecnik M, Anastasiou D, Hess D,
Hergovich A, Bichsel SJ, Hemmings BA Krek W (2005)
(2005) Venugopal J, Hanashiro K, Yang ZZ, The HRPT2 tumor suppressor gene
Human NDR kinases are rapidly activated Nagamine Y (2004) product parafibromin associates with
by MOB proteins through recruitment Identification and modulation of a caveo- human PAF1 and RNA polymerase II.
to the plasma membrane and phosphory- lae-dependent signal pathway that regu- Mol Cell Biol 25:5052-5060
lation. Mol Cell Biol 25:8259-8272 lates plasminogen activator inhibitor-1
in insulin-resistant adipocytes. Proc
Hergovich A, Schmitz D, Hemmings BA Nat Acad Sci USA 101:17120-17125 Group Barbara Hohn
(2006a)
The human tumor suppressor LATS1 Wanzel M, Kleine-Kohlbrecher D, Dube T, Kovalchuk I, Hohn B,
is activated by human MOB1 at Herold S, Hock A, Berns K, Park J, Thomson JA (2004)
the membrane. Biochem Biophys Res Hemmings BA, Eilers M (2005) Agrobacterium tumefaciens-mediated
Comm 345:50-58 Akt and 14-3-3eta regulate Miz1 to con- transformation of plants by the pTF-FC2
trol cell-cycle arrest after DNA damage. plasmid is efficient and strictly depen-
Hergovich A, Stegert MR, Schmitz D, Nature Cell Biol 7:30-41 dent on the MobA protein. Plant Mol Biol
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Dosage-dependent effects of Akt1/protein The INO80 protein controls homologous
Kalamidas SA, Kuehnel M, Peyron P, kinase Ba (PKBa) and Akt3/PKBg on recombination in Arabidopsis thaliana.
Rybin V, Rauch S, Kotoulas OB, thymus, skin, and cardiovascular Mol Cell 16:479-485
Hemmings BA, Gutierrez M, Anes E, and nervous system development in
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Synthesis and breakdown of cAMP Kovalchuk I, Hohn B (2005)
by phagosomes regulates actin assembly Dynamic response of plant genome
and fusion events during phagosome to ultraviolet radiation and other environ-
maturation: consequences for mycobac- mental stresses. Mut Res 57:235-247
teria. J Cell Sci (in press)
Group Frederick Meins Vaughn JP, Creacy SD, Routh ED, Etchegaray JP, Yang X, Debruyne JP,
Joyner-Butt C, Jenkins GS, Pauli S, Peters AH, Weaver DR, Jenuwein T,
Akbergenov R, Si-Ammour A, Blevins T, Nagamine Y, Akman SA (2005) Reppert SM (2006)
Amin I, Kutter C, Vanderschuren H, The DEXH protein product of the The polycomb group protein EZH2
Zhang P, Gruissem W, Meins F Jr, DHX36 gene is the major source is required for mammalian circadian
Hohn T, Pooggin MM (2006) of tetramolecular quadruplex G4-DNA clock function. J Biol Chem
Molecular characterization of geminivirus- resolving activity in HeLa cell lysates. 281:21209-21215
derived small RNAs in different plant J Biol Chem 280:38117-38120
species. Nucl Acids Res 34:462-471 Gonzalo S, Garca-Cao M, Fraga MF,
Venugopal J, Hanashiro K, Yang ZZ, Egua R, Cotter S, Peters AHFM,
Klahre U, Meins F Jr (2004) Nagamine Y (2004) Dean DC, Esteller M, Jenuwein T,
RNA silencing in plants Biolistic Identification and modulation of a Blasco M (2005)
delivery of RNAi reagents. In: Sohail M caveolae-dependent signal pathway that Role of the RB1 family in stabilizing
(ed) Gene silencing by RNA interference: regulates plasminogen activator inhibi- histone methylation at constitutive
technology and application. CRC Press, tor-1 in insulin-resistant adipocytes. Proc heterochromatin. Nature Cell Biol
Boca Raton, Fla, USA, pp 343-355 Nat Acad Sci USA 101:17120-17125 7:420-428
Venugopal J (2006)
Caveolar dysfunction leads to signal
transduction defects that are critical for
obesity-driven disorders. PhD thesis,
University of Basel
D. Braguer
Universit de la Mditerrane
Marseille, France
Microtubule dynamics and signal
transduction in tumor progression
Susan Gasser
Advanced seminars in epigenetics
Privatdozent
Masters in molecular biology Pico Caroni
Function and analysis of post- Systems neuroscience
translational protein modifications Signalling in neuroscience
Integrated biological systems Developmental neuroscience
Molecular biology of yeast and
Jan Hofsteenge
filamentous fungi
Protein modifications
Progress on supramolecular cellular
assemblies
Non-faculty
Nancy Hynes
Experimental cancer research Joy Alcedo
Experimental cancer research II Developmental neuroscience
Cell and molecular biology of cancer Helge Grosshans
Seminars on recent literature
Andreas Lthi in epigenetics
Signalling in the nervous system
Brian Hemmings
Genes, brain and behaviour
Seminars in growth control
Neurobiology foundation course SS2005/2006
Neurophysiology Seminars in growth control
The nervous system WS2005/2006
Seminars on new literature in
Thomas Oertner
neurobiology
Signalling in the nervous system
Postgraduate course in synaptic (Woods Hole, USA)
plasticity (University of Zurich)
Cell biology und neurobiology
Neuroscience (NCBS, Bangalore, India)
Antoine Peters
Patrick Matthias Protein modifications
Advanced immunology
Advanced seminars in epigenetics
Transcription regulation and gene
Seminars on recent literature
expression in eukaryotes
in epigenetics
Andrew Matus
Dirk Schbeler
Graduate course on neurobiology:
Current literature in epigenetics
Cortical maps
Protein modifications
Graduate course on neurobiology:
Consciousness Gene silencing
Evolution of brain and behaviour
Cell Biology of the neuronal
cytoskeleton (University of Stockholm)
MONOCLONAL ANTIBODIES
Susanne Schenk Ernst
Flow cytometry is an extremely flexible method for Quantitative fluorescence microscopy is increas-
characterising cells in suspension. Given a choice ingly valuable in modern biomedical research. New
of fluorochromes, fluorescence activated cell sort- imaging tools such as 2-Photon, FLIM, FRET and
ing (FACS) allows selection of cells based on e.g. live confocal imaging combined with powerful anal-
surface, cytoplasmic and nuclear antigens, GFP ex- ysis software go up to and beyond the limits of op-
pression, DNA content, cell cycle phase, or apop- tical resolution. The Microscopy and Imaging Core
tosis characters. The method can also measure in- Facility provides support at all steps of data prepa-
tracellular cytokines and the movement of Ca2+ ration, imaging, analysis and visualization, as well
ions, as well as discriminate alive and dead cells. as training in image acquisition and processing.
The Cell Sorting service operates an analytical Nine high-end imaging systems are used for
FACSCalibur equipped with a primary laser al- investigating and quantifying sample volumes,
lowing two light-scatter parameters and three shapes and densities as well as the locations, inter-
fluorescence channels to be measured and a actions and dynamics of molecules, organelles and
second laser for the excitation of dyes such as cells. Know-how and equipment are available for
APC or Cy5. A second MoFlo instrument is a high- multi-dimensional fluorescence microscopy, vol-
speed 4-way cell sorter with a 3-laser set-up, pro- ume time-lapse, confocal microscopy and spectral
viding sophisticated sorting based on multiple detection, multi-beam real-time confocal micros-
fluorescent dyes. copy, fluorescence recovery after photobleaching,
fluorescence resonance energy transfer, photo-
uncaging, photoactivation, spectral unmixing of
PROTEIN ANALYSIS
fluorescent labels, deconvolution, and environ-
Daniel Hess
mental control for live specimen imaging. Total
The Protein Analysis facility provides structural de- internal reflection microscopy and fluorescence
tails of proteins exploiting the latest developments correlation spectroscopy are offered in cooperation
in the fields of protein separation, quantification with almf@embl-heidelberg.
and mass spectrometry. Expertise is provided in the As an image without annotation is of low long-
preparation of samples for analysis (protein pre- term value, an image database has been developed
cipitation, labelling, etc.), in the separation of com- to allow the storage of experimental information
plex samples (2D gel electrophoresis and chroma- and microscope settings along with the raw image.
tography), in the quantification of protein expres- Both commercial packages in the form of plug-ins
sion, and in high-sensitivity identification of pro- and completely new, FMI-developed tools are used
teins and post-translational modifications by mass to analyse image data.
spectrometry.
This approach profits from the exponential
BIOINFORMATICS SUPPORT
growth of sequence databases with many fully se-
Michael Rebhan
quenced genomes. New developments in mass
spectrometry and separation have led to large in- The number of bioinformatics approaches,tools and
creases in sensitivity and speed of analysis. In the databases essential for current biological research
FMI, 2 D gel electrophoresis using two different increases almost daily. To exploit these tools ef-
units for isoelectric focusing (Multiphor II and ficiently, Bioinformatics Support provides a help-
IPGphor) and two SDS PAGE systems (Ettan DALT desk and training. The focus is on function predic-
12 and Protean II xi Cell) is coupled to appropriate tion, in-depth analysis of selected genes, transcripts
scanners and software for image analysis. High- and proteins, genomic data mining and understan-
sensitivity identification of proteins is carried out ding sequence-structure-function relationships. A
with three mass spectrometers: a TofSpec 2E for comprehensive environment for computational
rapid identification of single proteins by peptide biology analysis is being established in collabora-
mass fingerprinting, an LCQ Deca XP used in com- tion with the Biozentrum, University of Basel and
bination with capillary HPLC (fmol range), and an the Swiss Institute of Bioinformatics. The establish-
API300 combined with HPLC and equipped with ment of a protein structure facility will expand our
a nanospray source. capabilities by the end of 2006.
Applications
Please consult www.fmi.ch for full details of the
graduate studies programme with application forms
and deadlines and of openings for postdoctoral
fellows.
Bad
. Ba
sse
rstra FMI
hnh
lbee
Mau Maulbeerstrasse 66
Sch
of
Building 1066
wa
rzw
ald
alle
Ma
e
tte
nst
ras
se
se
as
l str
nta
Car Entrance se
Ro
Gate 1047
sse
Mes
tra
ns
se B
e
R ieh
asel
Gewerbeschule
From the Swiss /French railway station SBB / SNCF From the airport
Trams stop in front of the station. Take tram #1 (EuroAirport Basel / Mulhouse/ Freiburg)
or #2 from platform #3 (direction Bad.Bahnhof). Leave the baggage claim hall by the Swiss exit!
Trams leave every 5 minutes. Get off at the stop Bus: Take bus #30 to the Swiss/French railway
Gewerbeschule at Mattenstrasse. Cross the tram station SBB/SNCF. Buses leave every 15 minutes
tracks and follow Mattenstrasse for about 200 m, (more frequent at peak times). Trams stop in
then turn right into Maulbeerstrasse. You will find front of the railway station. Take tram #1 or #2
the FMI about 150 m along Maulbeerstrasse on from platform #3 (direction Bad. Bahnhof).
the right. Journey time is 10 minutes. Trams leave every 5 minutes. Get off at the stop
Gewerbeschule at Mattenstrasse. Cross the
tram tracks and follow Mattenstrasse for about
200 m, then turn right into Maulbeerstrasse.
From the Swiss /German railway station You will find the FMI about 150 m along
Basel Bad. Bahnhof Maulbeerstrasse on the right. Total journey time
The FMI is a short distance from the front en- is 35 minutes.
trance of this railway station. Cross the main road Taxi:The FMI is a short ride from the airport by
Schwarzwaldallee using the subway. Turn right, taxi. Journey time about 15 minutes.
and 150 m on your left turn into Maulbeerstrasse.
The FMI is about 100 m down the street on the
left. Journey time is 3 minutes.
By car
There is no parking space at the FMI entrance
area on Maulbeerstrasse. Parking is possible on
FMI telephone number for enquiries: the adjacent Syngenta site. Enter the Syngenta
+ 41 61 697 66 51 site at gate 1047 on Mattenstrasse (see map).
Register at the gate office. You will receive an
Street map ID badge and be allocated a parking space. Park
www.geo-bs.ch/stadtplan_stadtplan_karte.cfm the car and walk to the FMI (building 1066).