Tuesday, June 17, 2008
Hox Genes and Neurodevelopment
In the 1980s, scientists knew surprisingly little about the role genes play in the development of an embryo. The discovery of a particular group of genes, however, known as Hox genes, drastically improved our understanding of embryology. At the same time it revolutionized genetics and developmental biology.
In the 1890s, an English biologist named William Bateson was repeatedly amazed when he came across “freaks” of nature in his studies. These included examples like a moth born with wings where its legs should be, or an insect born with legs for antennae. In 1915, another biologist, Calvin Bridges, gave a name to these aberrations, calling them homeosis (meaning the transformation of one body part into another). Bridges had noticed homeosis in fruit flies that were born with an extra pair of wings. Intrigued, he kept this strain alive through selective mating.
In the 1980s, scientists were finally able to isolate the gene that was causing the extra wing mutation in the fruit fly. They traced it back to a small group of genes, which they called Hox genes. They found that, by manipulating these genes, they could create virtual monsters, such as flies with legs that came bursting out of the middle of their heads.
The creation of these monsters, however, helped to elucidate the function of Hox genes. Hox is short for homeobox, which is the name for the DNA sequence that these genes have in common. Hox genes become active in early embryonic development. Their job is to designate which parts of the embryo will turn into which body parts (legs, wings, head, etc.). Hox genes are so specific that, if one that controls limb development is transplanted to the head of the embryo, a limb will grow out of the head.
Scientists began to find these types of master control genes in every embryo, regardless of the organism. Even more surprisingly, the genes are considerably similar across species. Scientists found they could replace a defective Hox gene in a fly with one from a mouse without any ill effects. Hox genes and other master control genes are present in humans as well, and play the same role in embryonic development. This congruity across species indicates that Hox and master control genes are probably an ancient evolutionary mechanism, developed before much speciation took place, but still present and active.
While understanding Hox and master control genes has led to great advancements in the comprehension of embryonic development, the development of the brain has still remained a little unclear. Specifically, scientists have had trouble figuring out how specialized neurons in our brain are formed in one region, then migrate to the areas they eventually have to settle in in order to function properly.
A study published online this week in PloS Biology may shed some light on the issue, however, and Hox genes are an important part of the explanation. The authors of the study investigated pontine (from the pons) neurons in mice. Pontine neurons are formed in the rear of the brain and then must migrate in the brainstem to eventually become part of the precerebellar system. This is an area that is necessary for coordinated motor movement, and provides the cerebellum with its principal input. So the question is, once these pontine neurons are formed, how do they “know” they have to travel to the precerebellar region?
The researchers who conducted this study found Hox genes to be the guide that leads the neurons to their appropriate resting place. A specific Hox gene, Hoxa2, was found to influence neuronal migration, preventing them from going astray through the influence of a pathway of molecular signaling. The Hoxa2 gene regulates the expression of a particular receptor, known as Robo. The receptor binds to a chemical called Slit, which prevents the neurons from being drawn toward other chemoattracants. This allows the neurons to ignore outside influences and to travel directly to the precerebellar region, where they belong. When the scientists knocked out the Hoxa2 gene, the pontine neurons were unable to resist being drawn to chemoattractants and often didn’t reach their final destination.
This adds some insight into the process of neuronal migration, something that has been problematic to neuroscientists for years. It is just the beginning of the story, however. Not all of the neurons reacted to Hoxa2, suggesting there may be other Hox genes involved in brain development. Thus, scientists will continue to search for other Hox genes that are part of the process. The success of this study, however, at least provides an indication that Hox genes, some of the most highly conserved in our bodies, may also be responsible for some of the most important aspects of brain development.
Geisen, M.J., Meglio, T.D., Pasqualetti, M., Ducret, S., Brunet, J., Chedotal, A., Rijli, F.M., Zoghbi, H.Y. (2008). Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling. PLoS Biology, 6(6), e142. DOI: 10.1371/journal.pbio.0060142