Transcriptional regulation of aging in the adult neural stem cell niche

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DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate cellular and molecular mechanisms that specify the adult stem cell niche (SCN) in the CNS that harbors stem cells throughout life. The SCN is situated in the anterior subventricular zone where newly born neurons derived from adult stem cells migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) and differentiate into interneurons. The adult SCN consists of astrocytes and ependymal cells that line the ventricular surface of the neostriatum. Both these cell types are derived from an embryonic SCN in the lateral ganglion eminences (LGE). A constellation of transcription factors have been shown to regulate cell fate within distinct domains of the developing LGE. We have identified a fork head transcription factor (FOXJ1) which we show is expressed in a subset of embryonic progenitors in the LGE, and exhibits persistent expression in the postnatal SCN. Our proposed studies will shed light on novel mechanisms underlying differentiation of the SCN, and their concomitant role in regulation of adult stem cells and neurogenesis in the postnatal brain. It is now well established that the timing and proper development of radial glia and their astrocytic progeny are essential for normal CNS development and function. Our studies are unraveling the role of a subset of radial glial cells in the developing LGE which may give rise to a subset of layer specific neurons in the olfactory bulb. While a number of studies have focused on specification of neuronal progeny of radial glial cells in the cerebral cortices, molecular mechanisms that mediate the specification of ependymal cells and a subset of astrocytes that establish the adult SCN are completely unexplored. A comprehensive understanding of these mechanisms is of great interest as their manipulation in adult stem cells and/or the postnatal SCN may allow for production of new neurons and generation of guided neuronal migration to damaged or diseased brain regions, and potential correction of major birth defects such as hydrocephalus.