The formation of neural circuits in the central nervous system (CNS) depends on the ability of undifferentiated stem and progenitor cells to produce distinct classes of neurons and glial cells in a stereotyped manner. Our main objective is to understand the molecular details of how general aspects of cell cycle regulation and differentiation are coordinated with cell fate decisions. Previously, we identified a bHLH class transcriptional represser called Olig2 that is selectively expressed by motor neuron (MN) progenitors in the spinal cord, and involved in coordinating three key features of MN development: MN- specific gene expression, cell cycle exit, and general neuronal differentiation. Since Olig2 functions as a represser, we hypothesize that Olig2 must direct MN formation through its ability to shut off the expression of other important regulatory genes that themselves control the fate, proliferation, and differentiation of stem and progenitor cells in the CNS. The identity of these genes is currently not known. Using in vitro and in vivo assays of gene function in chick and mouse spinal cord, we will examine the regulated expression of three newly identified Olig2 targets and determine how these genes control different aspects of MN differentiation. First, we will determine the role of Hes genes in controlling the expression of the proneural bHLH protein Neurogenin2 and the overall capacity of MN progenitors to differentiate. Second, we will examine the role that Id genes play in inhibiting the function of Olig2 and Ngn2 to control the timing of MN differentiation. Third, we will test the role of PLZF, a transcription factor that controls stem cell self-renewal in other tissues, in maintaining spinal cord progenitors in an undifferentiated state. Together, these studies will provide significant insight into how stem and progenitor cells become specialized to generate specific cell types in the CNS, and provide a detailed understanding of how the processes of cellular division and differentiation are controlled. Insights into this process are important for our understanding of how different cell types in the nervous system are initially formed, and critical for current and future efforts to develop stem cells therapies to repair injured or diseased neural tissue.
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