This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Trauma and degenerative diseases of the central nervous system are prime targets of stem cell therapies. Successful stem cell therapy requires a thorough understanding of the mechanisms regulating neural cell differentiation and maturation. Towards this end, it is necessary to identify conditions that promote the differentiation of embryonic stem cells (ES cells) or neural stem cells (NSCs) and to develop methods to determine if the stem cell-derived progeny display normal phenotypic traits. A growing volume of research suggests that ES cells and NSCs can be induced to differentiate into cells that express molecular markers characteristic of a variety of mature neuronal and glial phenotypes and that these cells can, to at least a limited degree, functionally replace damaged cells. What remains to be determined is how expanded populations of stem cells can be stably differentiated into distinct cell types that could then be used to repopulate damaged tissues. Here, we propose that the chromatin remodeling factor, Brg1, regulates two critical stages of CNS development. First, it controls the switch in the commitment of NSC fate from neuronal to glial lineages. Second, it regulates the orderly maturation of neurons and innervation of target tissues. To test this model and the potential of targeting Brg1 to provide a stable source of NSC-derived cells to replace damaged spinal cord neurons, we aim: (1) To test the hypothesis that Brg1 regulates the differentiation and subtype specification of spinal motoneurons (MN) from NSCs; and (2) To test the hypothesis that Brg1 regulates MN innervation of target musculature. (3) To test how loss of Brg1 influences gliogenesis and neurogenesis in the cerebral cortex. (4) To test how Brg1 influences responses to CNS injury and inflammation.
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