REGULATION OF POSTNATAL CORTICAL MULTIPOTENT PROGENITORS

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We have isolated multipotent progenitor cells from the cerebral cortex independent of periventricular generative zones during the peak period of early postnatal gliogenesis. These progenitor species undergo cellular expansion and self-renewal in vitro in response to epidermal growth factor and can generate neurons and glia, including myelin protein-expressing oligodendrocytes. Glial progenitors derived from these multipotent progenitors express the neurotrophin-3 receptor, trkC, and application of neurotrophin-3 selectively promotes the expansion of oligodendrocyte progenitors that require additional environmental signals (ciliary neurotrophic factor, CNTF) for oligodendrocyte differentiation. Neurotrophin-3 can also induce the expression of the CNTFalpha receptor on glial progenitors derived from cortical multipotent cells, while bone morphogenetic proteins promote the generation of astrocytes and induce the expression of trkC on these progenitor species. In preliminary in vivo studies, we have also shown that transplanted cortical multipotent cells can undergo cellular expansion and give rise to glial and neuronal progeny. In addition, glial progenitors isolated from these multipotent cells proliferate in vivo and give rise to oligodendrocytes and astrocytes. Cortical injury enhances progenitor cell expansion and differentiation. In vitro analysis: 1. To define the cellular properties of epidermal growth factor-responsive cortical multipotent progenitors and their progeny: A. Do these progenitors undergo long-term self-renewal? B. What is the composition of neural lineage species derived from these multipotent cells? C. What are the cellular actions of neurotrophin-3 on oligodendroglial and astroglial development from glial progenitors derived from these multipotent cells? In vivo analysis: 2. To define the presence of appropriate early postnatal microenvironmental signals for cortical progenitor cell development: A. Are the cellular profiles of progenitor expansion, lineage restriction and differentiation equivalent in vitro and in vivo? B. Are glial-restricted progeny bipotent in vivo? C. Do different areas of the CNS neuraxis promote distinct progenitor cell response profiles? These studies will further our understanding of early progenitor cell regulatory events in neural lineage development during normal mammalian cerebral cortical maturation, identify pathologic mechanisms underlying a range of genetic and acquired neurologic disorders, and promote the development of novel regenerative strategies.