Biology of GFAP-expressing neural progenitors

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DESCRIPTION (provided by applicant): Substantial evidence indicates that the birth of new neurons (neurogenesis) continues throughout life in specific regions of the adult brain, including humans. The biology of the adult neural progenitors that give rise to new neurons is of considerable interest reflecting not only their potential functional roles, but also their potential for treatment or repair of neurological illness or injury. The identity and origin of adult neural progenitors are controversial. Experimental evidence suggests that some adult neural progenitors express glial fibrillary acidic protein (GFAP) and exhibit certain characteristics of astroglia. These observations raise questions and challenges. Given the fundamental roles of GFAP expressing astroglia in neural injury, disease and repair, it is important to understand the relationships, if any, between astroglia and adult neural progenitors. We have a longstanding interest in GFAP-expressing astroglia, and have developed transgenic mouse models to study these cells in neural injury and repair. Here, we apply these models to determine (i) the relative contribution, if any, of GFAP-expressing cells to adult neurogenesis in vivo and in vitro, (ii) whether all GFAP-expressing glia have neurogenic potential or whether this potential is associated with a subpopulation of cells that exhibits distinct phenotypic characteristics, and (iii) factors that regulate the neurogenic potential of GFAP-expressing neural progenitors, in particular after brain injury. To do so we use in vitro and in vivo techniques and several transgenic mouse models that allow (a) ablation of GFAP-expressing cells, (b) lineage analysis and fate mapping of progeny of GFAP-expressing cells, and (c) deletion of genes specifically from GFAP-expressing cells. Our preparatory work and preliminary data are consistent with several hypotheses including: (1) the predominant neural progenitors in adult forebrain express GFAP; (2) not all GFAP-expressing glia have neurogenic potential, neurogenic potential correlates with the presence of GFAP-expressing cells that exhibit certain phenotypic characteristics similar to radial glia; (3) the multipotent potential of GFAP-expressing progenitors can be manipulated by environmental conditions. Findings from studies proposed here will contribute fundamental information towards establishing the identity and regulation of adult neural progenitor cells, and towards defining the relationships between neural progenitors and the astroglia that respond to injury and disease. Understanding the biology of GFAP-expressing neural progenitors and their relationship to astroglia, which are widespread throughout the central nervous system, may reveal novel research avenues towards improving neural repair after injury or disease.