The role of Hox genes in development

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American Scientist has a nice review of Christiane Nüsslein-Volhard’s new book, Coming to Life: How Genes Drive Development.

Nüsslein-Volhard won the 1995 Nobel Prize for Medicine for her work on the genetic control of development in the fruit fly Drosophila melanogaster. The genetic mechanisms of development are better understood in this organism than in any other, and this understanding is based in no small part on the work of Nüsslein-Volhard. 

Because fruit flies have a short generation time and are small and easy to grow, they have been used extensively in genetics, in which they are model organisms. Naturally-occurring fruit fly mutants have been recognized for over a century, and mutations can easily be introduced into these organisms by exposing their eggs to ultraviolet radiation.  

The Hox genes, which were first discovered in fruit flies, encode transcription factors which are instrumental in regulating body formation during development. They belong to a family of genes called homeotic genes, which are characterized by a DNA sequence of approximately 180 base pairs, called the homeobox. This DNA sequence codes for the homeodomain, a DNA-binding domain consisting of about 60 amino acid residues. 

Hox genes are highly conserved in evolution, suggesting that they are of ancient origin. They appear to have arisen through duplication of an original Hox gene long ago. There was then another duplication which formed an ancestral cluster of 4 Hox genes; this cluster was in turn duplicated 4 more times in the vertebrate lineage. It is not known whether or not the number of Hox gene clusters bears any relation to the complexity of an organism. It can be speculated, however, that duplications or deletions of Hox gene clusters may have resulted in dramatic changes in species over short periods of time in evolution, and that this duplication was involved in evolution of the vertebrate body plan.   

Hox gene clusters control the polarity of the embryo, formation of the anterior-posterior body axis and body segmentation during embryogenesis in all species, including humans. The organization of Hox genes on the chromosomes reflects their anterior-posterior expression in the body.ant2.JPG

The homeotic genes were named such because when mutated they cause homeotic transformations, in which one segment or part of the body is replaced by another or duplicated. Mutations in the antennapedia gene cluster, for example, result in the formation of legs in place of antennae (left). Bithorax and postbithorax are involved in specifying the position of the haltere, a balancing organ on the third thoracic segment; a fruit fly with mutations in these genes has an additional set of wings in place of the haltere.

Vertebrates have four distinct Hox genes clusters, named A, B, C and D, which are involved in similar developmental processes. They are, for example, responsible for the segmentation of the hindbrain into rhombomeres, the transient structures which are involved in development of the cranial nerves. Hox genes are not, however, expressed in the anterior forebrain of vertebrates.

Humans have 39 Hox genes. Bone morphogenetic protein 4 (BMP4) and chordin are human homologs of the Drosophila Dpp gene, and are involved in specifying the identity of cells along the dorso-ventral axis of the developing neural tube. Chordin is expressed in the notochord and specifies the identity of floor plate cells in the developing neural tube, and BMP4 is involved in specifying the identity of roof plate cells. The dorso-ventral axis of the neural tube contains many different cell types, and the effects of these gene products are dependent on concentration, so that higher concentrations of BMP4 induce increasingly dorsal cells types. Diffusion of chordinand BMP4 from their sources creates a concentration gradient which specifies the identities of cells along the dorso-ventral axis. poly2.jpg 

Mutations in human Hox genes result in limb development defects. For example, the duplication of a digit (polydactyly) occurs as a result of mutations in the human Hoxd13 gene. Polydactyly is a congenital condition affecting about 1 in 500 live births. In the United States, there is a higher incidence of polydactyly in the Amish community than in the general population.

Polydactyls have six or more digits on their hands or feet; these supernumery digits sometimes consists of a small flap of soft tissue, and is sometimes a fully formed finger or toe. In some cases, the extra digit lacks joints and is useless; in others, it has limited dexterity or is fully functional. These extra digits are now normally surgically removed in early life, but throughout history, this condition has been associated with witchcraft and psychic powers.

Truncated mutations in human HoxA1 are known to disrupt development of the brainstem, inner ear and cardiovascular system, and to result in mental retardation and autism, and mutations in other Hox genes can also result in malformed genitals, and one Hox gene is known to be involved in regulating penis size.

In the 19th Century, Karl Ernst von Baer noticed the remarkable similarity between the early stage embryos of a wide variety of species, leading him to speculate on the evolutionary relationships between species. We now know that the molecular mechanisms of development are also remarkably similar, with Hox genes regulating body formation in all organisms, from the humble fruit fly to the human being.   

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