©Global Synergetic Foundation

Models of Development

How does structure emerge from a structureless state without an external

organising force?
We all start out as an undifferentiated clump of cells, all with
the same genetic code ?

Dr.S.S.D.Pandey
Global Synergetic Foundation
ssd@globalsynergetic.org
15th June 2008
 Dr.S.S.D.Pandey
Global Synergetic Foundation
 ©Global Synergetic Foundation

Self Organisation

Complex patterns can be produced by application of simple rules to

simple initial states.

In biological systems chemical signals combined with nonlinear local

interaction are able to produce very complex patterns.

Symmetry breaking: the initial undifferentiated state is

unstable. Feedback amplifies deviations, turning noise into
pattern.
 ©Global Synergetic Foundation

How to Make a Brain

Grow a large number of similar cells

Allow them to differentiate into different types depending on
the neighborhood.
Diffuse long range chemical signals
Let neurons send out connections towards their favorite
chemical(s).
Connect, and possibly remove failed cells and connections.
Repeat, add other kinds of plasticity.
 ©Global Synergetic Foundation

Reaction-Diffusion Systems

An important class of pattern forming systems consists of

chemicals diffusing and reacting with each other.

If the interactions are nonlinear and the diffusion coefficients

different, interesting instabilities result.

Can be modelled with partial differential equations or cellular

automata.
 Turing Patterns

Alan Turing 1952: Spontaneous symmetry breaking in

reaction-diffusion systems.

Diffusion of morphogens among identical cells ordered in a

Ring

Turing showed that when individually stable cells are

connected, diffusion can cause instability and pattern
formation
 Analysis of linear system

A basic example with two morphogens. Let x and y be their

deviations from equilibrium in each cell:

In order to get stability of isolated cells (no diffusion terms

The signs of the constant matrix are forced into one of these forms

Activator and depleted substrate

Activator and inhibitor

 The normal mode trick

The behavior of x and y can be analysed by expressing them

as normal modes

ξ and η can now be used instead; this is usually simpler

because different Fourier modes are decoupled
Doing the stability analysis for ξ and η gives:

As long as μ and ν are small the steady state x=y=0 is stable.

Beyond a certain point, one of the modes will become unstable, and
small disturbances will create an exponentially growing periodic
pattern.
Diffusion produces patterns instead of dissolving them!
This requires that μ is not equal to ν; lateral inhibition
 Meinhardt: Hydra Development

Model head development as activator-inhibitor pair with characteristic

length of the same order as body length.

Regeneration after division.

Symmetry breaking during growth
Effect of cutting
Diffusion works only over short scales.

Embryonic fields in which developmental decisions take place are smaller 1

mm and less than 100 cells across

The early local state is translated into a permanent cell state by changes in
gene expression

A hierarchy of genes that activate each other in turn

 Meinhardt: Segmentation

Several morphogens dependent on main gradient.

Location information important
Segmentation as gene activation
Reparation of a gap
Reversal
 Hamahashi and Kitano: Drosophila
Embryogenesis

Reaction diffusion of gene products regulating gene expression

Hierarchical arrangement of maternal, early and late genes

Based on known genes

 Meinhardt: Snail Shells

1D reaction diffusion system.

Complex shell patterning involves several
morphogens.
 2D Reaction-Diffusion Systems

Wide variety of patterns

Leaf primordia, fur patterns, vasculature, retinotopic maps
Barrio et. al.: Fish Patterns
Spots and leaf primordia
 Vascular networks

Cells differentiate when a signal reaches a threshold

Signal production is dependent on a substrate that is
removed by differentiated cells
 Hentschel & Fine:
Activity Dependent Dendritic Morphogenesis

Calcium as a morphogen.
Sub membrane calcium concentration controls the local growth
velocity.
Excitable membrane. Positive feedback for calcium influx.
Calcium catalytic growth produces branching patterns
 Hely, Graham and van Ooyen:
Dendrite branching
Elongation and branching due to MAP2 bound to microtubuli
 Axogenesis
Axons seek out their target using growth cones sensing
chemical gradients.
 How far can a gradient guide?

Three constraints:
Too low concentration: almost no receptors will be bound
Too high concentration: all receptors will be bound
Concentration difference across cone must be larger than noise

Relative difference:

Absolute difference:

Results in a maximum distance of 1mm for a diffusing signal,

1cm for an optimally distributed substrate-bound signal.
Fleischer: Axons following chemical gradients
Bundling Model of Hentschel and van Ooyen
(Model I)

Chemoattractant towards target cells

Chemoattractant from growth cones causes bundling

Chemorepellant from growth cones, dependent on target cell

chemoattractant, causes dispersion near target

Cone growth towards chemical gradient.

 Model II

Instead of chemical signals from growth cones, physical

attachment when they get close enough.

Attachment strength depends on chemo attractant from

target.

Random axon movement.

 Results

Model I produces nice fasciculation and unbundling near target.

Topological Organisation.

Model II does not bundle globally, does not unbundle. Pathfinder cells.
Phenomenological Development Modeling

Cellular Automata
Diffusion Limited Aggregation
Lindenmeyer-systems
 Conclusion

Complex patterns and Organisation can be

achieved by simple rules.

Diffusion of chemo attractants or morphogens can

induce
long-range order.

More and more morphogens and genetic

networks have been identified.

A lot of data is waiting for modeling.

Thank You very much

Dr.S.S.D.Pandey
ssd@globalsynergetic.org

Centre for Studies in Complexity

Global Synergetic Foundation

www.globalsynergetic.org