Early development of the mammalian retina proceeds through molecular and cellular steps in which cells exit the mitotic cell cycle and terminally differentiate into one of seven basic types of neurons or glia. Abnormalities in this process are manifested in different diseases, including optic nerve aplasia, congenital glaucoma or cone/rod dystrophic syndromes. Before treatments or therapies can be designed to alleviate or cure such conditions, the primary biologic mechanisms of retinal development must be learned. This proposal uses embryological, genetic, neurobiological, immunohistochemical, and molecular methods to explore the regulation and function of mouse basic helix-loop-helix (bHLH) proteins during mouse retinal development. In particular the Ath5/ATOH7 gene (Math5 in mice) is one such molecule that is required for retinal ganglion cell (RGC) specification and differentiation. Math5-/- mice completely lack RGCs and optic nerves postnatally and exhibit increases in both cone photoreceptor and amacrine neurons.
The specific aims of this proposal will investigate how Math5 function in embryonic retinal progenitors affects the mitotic cell cycle state of these cells, specifically whether cell cycle progression is aberrant in Math5-/- cells. In addition we propose to test the multipotency of Math5 retinal progenitors by targeted replacement of Math5 with another bHLH gene that promotes bipolar fates, Mash1. In this proposal we present preliminary evidence for both trans-acting factors and cis-acting DNA sequences that control the expression pattern of Math5 during retinal development.
We aim to further characterize this molecular genetic pathway in proposed experiments. Vertebrate Ath5 genes promote RGC formation in all tested model organisms and their Drosophila counterpart, atonal promotes R8 photoreceptor formation in the fly eye. However, each gene does not orchestrate these specification processes identically and we will test whether molecular genetic regulation of Math5 is conserved or divergent with that of the Drosophila atonal gene. The proposed studies will yield valuable insight into the basic biologic mechanisms of retinal neuron formation so that the causes of diseases of the retina will eventually be uncovered. ? ?
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