The proposal is concerned with understanding how retinal ganglion cells are specified in the vertebrate retina. Although the pattern of retinal development has been well described, very little is known about the molecular events that control the arrangement, commitment, and differentiation of retinal neurons. One approach to understanding retinal development is to define specific components of essential genetic regulatory events. This proposal focuses on three closely related POU-domain genes, brn-3a, brn-3b, and brn-3c, which have been implicated in cell fate specification during neuronal development. These genes are expressed in the murine retina specifically within subsets of ganglion cells and also in dorsal root and trigeminal ganglia, and in selected regions of the brain. Targeted disruptions have shown that brn-3b is required for the development of a large set of retinal ganglion cells whereas brn-3a and brn-3c are essential for the development of somatosensory and auditory neurons, respectively. Initial experiments have led to the hypothesis that Brn-3b is part of a decision-making process that acts to control whether or not a post-mitotic neuroblast adopts a ganglion cell fate.
Three specific aims are proposed to determine more precisely the role that Brn-3b plays in retinal ganglion cell development and its relationship to Brn-3a and Brn-3c: (1) the fate of brn-3b-expressing cells during retinal development will be determined in wild type and brn-3b-deficient embryos using a brn-3b(-/-)lacZ gene inserted into brn-3b locus as a marker for brn-3b positive cells; (2) the functional equivalence of Brn-3a, Brn-3b and Brn-3c in retina will be tested by homologous recombination of brn-3a and brn-3c sequences into brn-3b locus; and (3) the ability of Brn-3b to convert uncommitted retinal neuroblasts to a ganglion cell fate will be assessed by ectopic retroviral expression of brn-3b in the developing retinas of chick embryos.
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