Mutations in certain human genes cause cell number defects in specific regions of the central nervous system (CNS). These changes cause developmental anomalies that severely compromise CNS function. Evidence is starting to emerge that several of these mutations are in genes that regulate proliferation. However, the mechanisms by which they function are poorly understood. To address this, we are studying the regulation of proliferation during murine retinal development. The developing mouse retina is well established as a model system for studying CNS development, and genetic mutations have been identified that cause proliferation defects specific to the retinal neuroepithelium. Identifying how these mutations alter retinal proliferation may help us to understand how region specific regulation of proliferation occurs throughout the CNS neuroepithelium. Chx10 is a homeobox gene expressed in retinal progenitor cells and null mutations cause congenital microphthalmia in humans and mice. In the retina, there is a severe deficit in cell number, and this is due in large part to a reduction in proliferation during development. Two cell cycle genes, Cyclin D1 and p27(Kip1), are misregulated in the Chx10 mutant retina, and genetic inactivation of p27(Kip1) significantly restores cell number and alleviates the severity of the microphthalmia. These findings establish a link between Chx10 and the cell cycle in retinal progenitor cells. Our hypothesis is that Chx10 could have multiple functions in retinal progenitor proliferation.
In Aim 1 we will determine if Chx10 regulates proteins required for G 1 progression.
In Aim 2, we will determine which phases of the cell cycle are dependent on Chx10. For these Aims, Chx10 null mice will be mated with mice containing null alleles of critical cell cycle genes to produce combinatorial mutants.
In Aim 3, we will determine if Chx10 is required for mitogen signaling in retinal progenitor cells using primary cell culture. These studies have the potential to identify the functions of Chx10 in regulating retinal progenitor proliferation, and this information can be applied to other areas of the CNS where proliferation is a key determinant of development and function.
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