Multiple pathological conditions result from degeneration of the central nervous system. These include neurodegenerative diseases including Alzheimer's and Parkinson's, as well as neoplastic pathologies such as glioma and oligodendrogioma. In this context increasing interest surrounds the potential of endogenous neural progenitor cells to repair or replace damaged neural tissue. Recently, we have observed that while the brains of Id2 -/- mice appear to develop normally, adults have smaller olfactory bulbs. We hypothesize that while Id2 appears dispensable for brain development, it may have an important post-developmental role in adult neurogenesis. Our preliminary data demonstrate morphological defects in the olfactory bulbs of Id2 null mice consistent with a decrease in adult neural progenitor derived neurogenesis. In addition, we observe that Id2 null neural progenitor cells display a striking phenotype characterized by loss of self-renewal and premature neural differentiation in vitro. In this proposal, we outline a series of experiments to better understand the molecular mechanisms of Id2 in maintenance of the adult neural progenitor pool. Here we propose to employ both in vivo and in vitro studies in order to monitor the ability of Id2 null neural progenitors to self-renew and contribute specifically to adult neurogenesis. Further, we propose to dissect the role of Id2 in maintenance of the neurogenesis on a molecular level by investigating the ability of Id2 to block the neurogenic activities of NeuroD1 via direct upstream inhibition of Neurogenin. This research proposal represents a novel analysis that is designed to establish a specific role for Id2 in adult neurogenesis that is distinct from other Id genes. Following development, a population of multi-potent neural progenitor cells is maintained in the adult brain. These cells contribute to olfaction, respond to ischemic injury and are putatively linked to cancer. This proposal is designed to investigate the role of Id2 in maintaining the plasticity of the progenitor cell pool. These experiments are immediately relevant to realization of the therapeutic potential of these unique cells. ? ?
|Havrda, Matthew C; Harris, Brent T; Mantani, Akio et al. (2008) Id2 is required for specification of dopaminergic neurons during adult olfactory neurogenesis. J Neurosci 28:14074-86|