June 16, 2008 Pontine neurons are generated in the rear part of the brain and ultimately end up in the cerebellum, a region in the brain responsible for coordinating the senses and motor functions in the body. How these neurons make the journey across the brain has, until now, been somewhat of a mystery. In a new paper authors Filippo Rijli and colleagues demonstrate that pontine neuron migration in mice is controlled by specific Hox genes. They show that by knocking out the expression of the Hoxa2 gene the path of the neurons changes, causing them to end up in the wrong part of the brain.
Hox genes are crucial in the orchestration of organized growth in organisms ranging from plants to humans. The authors have identified a specific Hox gene, Hoxa2, which controls the pontine neurons' responsiveness to chemicals that attract and repel them, thus telling them where to go in the brain. The authors found that when the Hoxa2 gene was knocked out, the pontine neurons went to the bottom of the brainstem instead of going to the cerebellum.
To explain in detail, the Hoxa2 gene controls expression of the receptor, Robo. Robo is bound to the chemical, Slit, which prevents migrating neurons from responding to chemoattractants. The authors found that in knocking out Hoxa2, pontine neurons become insensitive to Slit signaling: the neurons ignore the repellant signal and head prematurely toward the chemoattractant, guiding them into the wrong part of the brain. The study also shows that the absence of Slit or Robo causes the same type of abnormal migrations caused by the absence of Hoxa2--further evidence that all three are integral to the same system.
Although this paper resolves some of the mystery of the neuron migration route, there is still more to explore. The authors found that not all neurons react to a loss of Hoxa2, suggesting these genes function in a specific manner and opening the search for other Hox genes that affect neuronal migration and the development of the mammalian brain.
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- Geisen et al. Hox Paralog Group 2 Genes Control the Migration of Mouse Pontine Neurons through Slit-Robo Signaling. PLoS Biology, 2008; 6 (6): e142 DOI: 10.1371/journal.pbio.0060142
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