NEUROFIBROMIN REGULATION OF NEURAL STEM CELL FUNCTION IN VITRO AND IN VIVO

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Normal mammalian brain development involves the regulated growth of progenitor cells and their differentiation into specialized cell types. Abnormalities in progenitor cell function during embryogenesis can lead to inappropriate expansion of stem cell populations and abnormal glial maturation, and potentially result in a number of brain abnormalities, including the formation of brain tumors in children. Neurofibromatosis type 1 (NF1) is one of the most common genetic conditions in which affected children develop glial cell tumors (optic pathway gliomas). Using NF1 as a model system to study neural stem/progenitor cell (NSC) function in vitro and in vivo, we have shown that loss of Nf1 protein (neurofibromin) function in embryonic NSCs results in (1) increased NSC proliferation and self-renewal and (2) increased glial lineage expansion. Based on our experimental observations, we hypothesize that neurofibromin is required for NSC maintenance and glial cell maturation in vivo. In this proposal, we have designed complementary in vitro and in vivo experiments to determine how neurofibromin controls NSC maintenance and glial cell differentiation. The overall objective of this proposal is to employ laboratory-generated genetically-engineered Nf1 mutant mice and Nf1-deficient NSCs as tractable experimental platforms to define the critical control mechanisms that govern NSC function in the developing central nervous system.