This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mechanisms regulating altered gene transcription in neural stem cells (NSCs) as they transition from states of symmetric, self-renewing cell division to asymmetric division, resulting in the birth of neurons and glial cells in the central nervous system (CNS), are largely unknown. Recent evidence supports the notion that the SWI/SNF family of chromatin remodeling factors may influence cell type-specific patterns of transcriptional activation or repression during CNS development. One SWI/SNF subunit, called brahma-related gene-1 (Brg1), is expressed throughout the developing CNS in a pattern that suggests critical roles in the genesis of both neurons and glia. Our preliminary data are consistent with the hypotheses that (1) loss of Brg1 disturbs the normal balance governing how and when NSCs generate neuronal and glial progenitors, and (2) Brm compensates for the loss of Brg1 in at least some CNS cell types. As SWI/SNF factors influence both the activation and repression of specific classes of genes, we further predict that Brg1 and Brm influence genetic programs that dictate when cell type-specific genes are activated, as well as genes that influence NSC survival and cell cycle progression. To address these possibilities, we aim to: 1) test if Brg1 regulates NSC cell cycle progression and survival during neurogenesis and gliogenesis, 2) test if Brm and Brg1 together influence neuronal differentiation, and 3) determine which genes are transcriptionally repressed or activated by Brg1 and Brm in NSCs.
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