Analysis of a novel regulator of vertebrate retinal neurogenesis

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DESCRIPTION (provided by applicant): A number of congenital eye disorders stem from alterations in early development, including proliferation and differentiation of progenitors within the neural retina, although in many cases the mechanisms underlying these disorders is not understood. By defining the mechanisms controlling normal retinal neurogenesis, we may gain a better understanding of how these processes are disrupted in pathological situations. bHLH transcription factors play a pivotal role in retinal neurogenesis, but remarkably little is known about how they control the process of retinal neuron differentiation. We have identified a new gene, sbt1, which encodes a novel protein that is expressed in the developing Xenopus nervous system and which is regulated by proneural bHLH activity. Our preliminary results indicate that sbt1 is an essential regulator of retinal neurogenesis in Xenopus. We have identified a mouse ortholog of this gene, and showed that it is also expressed in the nervous system and has a conserved ability to regulate retinal neuron differentiation. Here we propose to develop two new directions for the analysis of sbt1 function. In Specific Aim 1 we will initiate a study of sbt1 during mouse retinal development by performing a detailed analysis of sbt1 expression, and determining whether its expression depends upon proneural bHLH factors. In Specific Aim 2 we will analyze subcellular localization of sbt1 and define protein partners for this novel protein. The experiments in this proposal will provide the conceptual framework for an in-depth genetic study of sbt1, a novel and exciting gene that appears to be a key regulator of neuronal differentiation in the developing retina. A long-term hope is that we may ultimately be able to manipulate the differentiation of retinal stem cells or progenitors to treat retinal degenerative diseases. Our work will contribute to this effort by characterizing the molecular mechanisms underlying retinal neuron differentiation and cell fate specification.