Hox gene

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Hox genes are a group of related genes that specify the anterior-posterior axis and segment
identity of metazoan organisms during early embryonic development. These genes are critical for
the proper number and placement of embryonic segment structures (such as legs, antennae, and
eyes).

Contents
[hide]

1 The homeobox
2 Sequence conservation

3 The homeodomain

4 Genes Regulated by Hox Genes

5 Enhancer sequences that bind the homeodomain

6 Regulation of Hox genes

7 Homeotic mutations

8 Colinearity of Hox genes

9 Classification of Hox genes

10 Phylogenetic distribution of Hox genes

o

10.1 Human genes

11 History

12 See also

13 References

14 External links

[edit] The homeobox

Hox genes are defined by a DNA sequence known as the homeobox, which is a sequence of 180
nucleotides that code for a protein domain known as the homeodomain.
The consensus polypeptide chain is [1] (typical intron position noted with dashes)
RRRKRTA-YTRYQLLE-LEKEFLF-NRYLTRRRRIELAHSL-NLTERHIKIWFQN-RRMKWKKEN
The first genes found to encode homeodomain proteins were Drosophila developmental control
genes, in particular Hom-C genes, from which the name homeobox was derived. However, many
homeobox genes are not homeotic genes; the homeobox is a sequence motif, while "homeotic" is
a functional description for genes that cause homeotic transformations.[1]

[edit] Sequence conservation

The homeodomain protein motif is highly conserved across vast evolutionary distances. The
functional equivalence of Hox proteins can be demonstrated by the fact that a fly can function
perfectly well with a chicken Hox protein in place of its own.[2] This means that, despite having a
last common ancestor that lived over 670 million years ago[3], a given Hox protein in chickens
and the homologous gene in flies are so similar that they can actually take each other's places.
Although the protein sequence is highly conserved, the DNA sequence from which it is made is
slightly less so, a result of codon degeneracy (i.e., more than one codon codes for the same
amino acid). The reason for this high level of conservation is related to the function of these
proteins. Hox genes set up the basic regional layout of an organism, so that eyes form on the
head and not on the abdomen, and limbs form at the sides and not on the head. Even a single
mutation in the DNA of these genes can have drastic effects on the organism (see Homeotic
mutations, below), and so these genes have changed relatively little over time.

[edit] The homeodomain

The protein products of Hox genes belong to a class of proteins known as transcription factors,
all of which are capable of binding to DNA, thereby regulating the transcription of genes. The
homeobox sequence codes for a 61 amino acid helix-turn-helix protein known as the
homeodomain. The homeodomain acts as an "on/off" switch for gene transcription by binding to
specific sequence enhancers of a gene, which either activates or represses the gene. The same
Hox protein can act as a repressor at one gene and an activator at another. For example, in flies
(Drosophila melanogaster) the protein product of the Hox gene Antennapedia activates genes
that specify the structures of the 2nd thoracic segment, which contains a leg and a wing, and
represses genes involved in eye and antenna formation[4]. Thus, legs and wings, but not eyes and
antennae, will form wherever the Antennapedia protein is located.

[edit] Genes Regulated by Hox Genes

Homeobox gene expression in Drosophila melanogaster.

Hox genes act at many levels within developmental gene hierarchies: at the "executive" level
they regulate genes that in turn regulate large networks of other genes (like the gene pathway that
forms an appendage). They also directly regulate what are called realisator genes or effector
genes that act at the bottom of such hierarchies to ultimately form the tissues, structures, and
organs of each segment. Segmentation involves such processes as morphogenesis (differentiation
of precursor cells into their terminal specialized cells), the tight association of groups of cells
with similar fates, the sculpting of structures and segment boundaries via programmed cell death,
and the movement of cells from where they are first born to where they will ultimately function,
so it is not surprising that the target genes of Hox genes promote cell division, cell adhesion,
apoptosis, and cell migration[5].
Examples of targets
Organism Target gene
Normal function of target gene
Regulated by
activates gene pathway for limb
ULTRABITHORAX[6]
distal-less
formation
(represses distal-less)
activates gene pathway for limb
ABDOMINAL-A[6]
distal-less
formation
(represses distal-less)
triggers cell shape changes in the gut that ULTRABITHORAX[7]
decapentaplegic are
(activates
required for normal visceral morphology decapentaplegic)
Drosophila
Apoptosis: localized cell death creates the
segmental
DEFORMED[8]
reaper
boundary between the maxilla and
(activates reaper)
mandible of the head
prevents the above cell changes in more
ABDOMINAL-B[9]
dapentaplegic posterior
(repress decapentaplegic)
positions
Mouse
EphA7
Cell adhesion: causes tight association of HOX-A13[5]
cells in
(activates EphA7)
distal limb that will form digit, carpal and

Cdkn1a

tarsal bones
Cell cycle: differentiation of
myelomonocyte cells into
Hox-A10[10]
monocytes (white blood cells), with cell (activates Cdkn1a)
cycle arrest

[edit] Enhancer sequences that bind the homeodomain

The DNA sequence that is bound by the homeodomain protein contains the nucleotide sequence
TAAT, with the 5' terminal T being the most important for binding[11]. This sequence is conserved
in nearly all sites recognized by homeodomains, and probably distinguishes such locations as
DNA binding sites. The base pairs following this initial sequence are used to distinguish between
homeodomain proteins, all of which have similar recognition sites. For instance, the nucleotide
following the TAAT sequence is recognized by the amino acid at position 9 of the homeodomain
protein. In the maternal protein Bicoid, this position is occupied by lysine, which recognizes and
binds to the nucleotide guanine. In Antennapedia, this position is occupied by glutamine, which
recognizes and binds to adenine. If the lysine in Bicoid is replaced by glutamine, the resulting
protein will recognize Antennapedia-binding enhancer sites[12]

[edit] Regulation of Hox genes

Just as Hox genes regulate realisator genes, they are in turn regulated themselves by gap genes
and pair-rule genes, which are in their turn regulated by maternally-supplied mRNA. This results
in a transcription factor cascade: maternal activate gap or pair-rule genes; gap and pair-rule genes
activate Hox genes; then, finally, Hox genes activate realisator genes that cause the segments in
the developing embryo to differentiate.
Regulation is achieved via protein concentration gradients, called morphogenic fields. For
example, high concentrations of one maternal protein and low concentrations of others will turn
on a specific set of gap or pair-rule genes. In flies, stripe 2 in the embryo is activated by the
maternal proteins Bicoid and Hunchback, but repressed by the gap proteins Giant and Kruppel.
Thus, stripe 2 will only form wherever there is Bicoid and Hunchback, but not where there is
Giant and Kruppel[13].
MicroRNA strands located in hox clusters have been shown to inhibit more anterior hox genes
("posterior prevalence phenomenon"), possibly to better fine tune its expression pattern.[14]
Non-coding RNA (ncRNA) has been shown to be abundant in Hox clusters. In humans, 231
ncRNA may be present. One of these, HOTAIR, silences in trans (it is transcribed from the
HOXC cluster and inhibits late HOXD genes) by binding to Polycomb-group proteins (PRC2).[15]
The chromatin structure is essential for transcription but it also requires the cluster to loop out of
the chromosomal territory.[16]
Quantitative PCR has shown several trends regarding colinearity: the system is in equlibrium and
the total number of transcripts depends on the number of genes present according to a linear
relationship [17].

[edit] Homeotic mutations

Incorrect expression of Hox genes can lead to major changes in the morphology of the
individual. Homeotic mutations were first identified in 1894, when William Bateson noticed that
floral stamens occasionally appeared in the wrong place; he found four example flowers in which
the stamens would grow in the place where petals normally grow.
In the late 1940s, Edward Lewis began studying homeotic mutation on Drosophila melanogaster
which caused bizarre rearrangements of body parts. Mutations in the genes that code for limb
development can cause deformity or lead to death. For an example, mutations in the
Antennapedia gene cause legs to develop on the head of a fly instead of the antenna.[18]
Another famous example in the Drosophila melanogaster is the mutation of the Ultrabithorax
Hox gene, which specifies the 3rd thoracic segment. Normally, this segment displays a pair of
legs and a pair of halteres (a reduced pair of wings used for balancing). In the mutant lacking
functional Ultrabithorax protein, the 3rd thoracic segment now expresses the same structures
found on the segment to its immediate anterior, the 2nd thoracic segment, which contains a pair
of legs and a pair of (fully developed) wings. These mutants sometimes occur in wild
populations of flies, and it was these mutants that led to the discovery of Hox genes.

[edit] Colinearity of Hox genes

The various Hox genes are situated very close to one another on the chromosome in groups or
clusters. Interestingly, the order of the genes on the chromosome is the same as the expression of
the genes in the developing embryo, with the first gene being expressed in the anterior end of the
developing organism. The reason for this colinearity is not yet completely understood. The
diagram above shows the relationship between the genes and protein expression in flies.

[edit] Classification of Hox genes

Hox genes in different phyla have been given different names, which has led to confusion about
nomenclature. The complement of Hox genes of the Ecdysozoa (arthropods,nematodes, etc) is
made up of two clusters, the Antennapedia complex and the Bithorax complex, which together
are referred to as the HOM-C (for Homeotic Complex). Hox genes in deuterostomes
(echinoderms, chordates) are correctly referred to as Hox genes, and are arranged in four
clusters: Hoxa, Hoxb, Hoxc, and Hoxd. Although it is technically incorrect to refer to homeotic
genes in non-deuterostome phyla as "Hox genes", the practice of using "Hox" in place of "HomC" is now acceptable even in the scientific literature.

[edit] Phylogenetic distribution of Hox genes

In Ecdysozoa, there are approximately ten Hox genes. Vertebrates have four duplicates
(paralogues) of these ten genes, known as Hoxa, Hoxb, Hoxc, and Hoxd. These four paralogous
clusters are a consequence of the ancestral vertebrate genome being twice duplicated in its

entirety[19]. The first occurred before the Cnidaria-Bilateria split, the second during the evolution
of the fishes.[2] The arrows represent Hox genes arrayed along a chromosome. The bottom line
represents the ten Hox genes seen in most invertebrates, and is the ancestral complement of the
vertebrates. The top four lines represent the four duplicated clusters of these ten genes seen in
vertebrates. In order from left to right (anterior to posterior), they are: labial, proboscipedia,
zerknullt, Deformed, Sex combs reduced, fushi tarazu, Antennapedia, Ultrabithorax, AbdominalA and Abdominal B. Arrows with the same color came from the same ancestral gene.
Although these vertebrate genes are duplicates of the same genes seen in the Ecdysozoans, the
four copies are not actually identical. Each copy has accumulated its own unique mutations over
time, producing proteins with distinct functions. Some have actually been deleted entirely or
duplicated again in certain vertebrate groups.
For example, Hoxa and Hoxd are involved in the segment identity along the limb axis. Hox
expression in the limb has two phases, an early wave of expression for the arm and a late wave
for the digits, which involves Hoxd 8 13 and has a separate regulatory region 5 of Hoxd 13
which is not found in teleost fish [20].

[edit] Human genes

Humans contain Hox genes in four clusters:
cluster chromosome genes
HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7,
HOXA chromosome 7
HOXA9, HOXA10, HOXA11, HOXA13
chromosome HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXB7,
HOXB
17
HOXB8, HOXB9, HOXB13
chromosome HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10, HOXC11,
HOXC
12
HOXC12, HOXC13
HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11,
HOXD chromosome 2
HOXD12, HOXD13

[edit] History
Christiane Nsslein-Volhard and Eric F. Wieschaus identified and classified 15 genes of key
importance in determining the body plan and the formation of body segments of the fruit fly
Drosophila melanogaster. Edward B. Lewis studied the next step - Hox genes that govern the
development of a larval segment into a specific body segment. Homeotic means that something
has been changed into the likeness of something else. Lewis found a colinearity in time and
space between the order of the genes in the bithorax complex and their affected regions in the
segments. For their work they were awarded the Nobel Prize in Physiology or Medicine in 1995.
Further information: Nobel foundation website
File:L-fly-larva.gif

[edit] See also

Homeobox
Morphogenesis

[edit] References
1. ^ Burglin, T.(2005). The Homeobox Page. http://www.cbt.ki.se/groups/tbu/homeo.html#Structure
%20of%20the%20homeodomain
2. ^ Lutz, B.; H.C. Lu, G. Eichele, D. Miller, and T.C. Kaufman (1996). "Rescue of Drosophila
labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is
phylogenetically conserved". Genes & Development 10: 176184. doi:10.1101/gad.10.2.176.
3. ^ Ayala, F.J.; A. Rzhetskydagger (20 January 1998). "Origin of the metazoan phyla: Molecular
clocks confirm paleontological estimates". Proc Natl Acad Sci 95 (2): 60611.
doi:10.1073/pnas.95.2.606.
4. ^ Cesares and Mann 1998; Plaza et al. 2001
5. ^ a b Pearson, JC, Lemons, D. and McGinnis, W. Modulating Hox gene functions during animal
body patterning. Nature Rev. Genet. 6, 893904 (2005).
6. ^ a b Vachon, G. et al. Homeotic genes of the bithorax complex repress limb development in the
abdomen of the Drosophila embryo through the target gene Distal-less. Cell 71, 437450 (1992).
7. ^ Capovilla, M. & Botas, J. Functional dominance among Hox genes: repression dominates
activation in the regulation of dpp. Development 125, 49494957 (1998).
8. ^ Lohmann, I., McGinnis, N., Bodmer, M. & McGinnis, W. The Drosophila Hox gene Deformed
sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 110, 457466
(2002).
9. ^ Capovilla, M. & Botas, J. Functional dominance among Hox genes: repression dominates
activation in the regulation of dpp. Development 125, 49494957 (1998).
10. ^ Bromleigh, V. C. & Freedman, L. P. p21 is a transcriptional target of HOXA10 in
differentiating myelomonocytic cells. Genes Dev. 14, 25812586 (2000).
11. ^ Gilbert, Developmental Biology, 2006
12. ^ Hanes and Brent 1989, 1991
13. ^ Small S, 1992. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 1992
Nov;11(11):4047-57
14. ^ Lempradl A, Ringrose L. 2008 How does noncoding transcription regulate Hox genes?
Bioessays. 30(2):110-21.
15. ^ Rinn JL et al., 2007. Functional demarcation of active and silent chromatin domains in human
HOX loci by noncoding RNAs. Cell. 129(7):1311-23

16. ^ Fraser P, Bickmore W. 2007. Nuclear organization of the genome and the potential for gene
regulation. Nature. 447(7143):413-7.
17. ^ Montavon et al. 2008. Modeling Hox gene regulation in digits: reverse collinearity and the
molecular origin of thumbness. Genes Dev. 22(3):346-59
18. ^ Pierce, Benjamin A. Genetics:A Conceptual approach.2nd edition
19. ^ Dehal P, Boore JL (2005) Two Rounds of Whole Genome Duplication in the Ancestral
Vertebrate. PLoS Biol 3(10): e314
20. ^ Deschamps J. 2007. Ancestral and recently recruited global control of the Hox genes in
development. Curr Opin Genet Dev. 17(5):422-7

[edit] External links

The Homeotic Selector Genes in Developmental Biology, 6th Edition by Scott F. Gilbert
(2000) Published by Sinauer Associates, Inc. ISBN 0-87893-243-7.
Drosophila labial - The Interactive Fly

Drosophila proboscipedia - The Interactive Fly

Drosophila zerknullt - The Interactive Fly

Drosophila Deformed - The Interactive Fly

Drosophila Sex combs reduced - The Interactive Fly

Drosophila fushi tarazu - The Interactive Fly

Drosophila Antennapedia - The Interactive Fly

Drosophila Ultrabithorax - The Interactive Fly

Drosophila abdominal A - The Interactive Fly

Drosophila Abdominal B - The Interactive Fly

Retrieved from "http://en.wikipedia.org/wiki/Hox_gene"

Categories: Developmental genes and proteins
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