Self -renewal of central nervous system stem cells.

Neural stem cells are defined by their ability to self-renew and undergo multilineage differentiation. We found that Bmi-1 is required for the self-renewal of central nervous system stem cells, and that in the absence of Bmi-1, stem cells become profoundly depleted by adulthood. Restricted neural progenitors from the forebrain proliferated normally in the absence of Bmi-1, revealing a molecular distinction between pathways that regulate stem cell self-renewal and those that regulate the proliferation of some types of restricted progenitors. In the absence of Bmi-1, both products of the Ink4a-Arf senescence-associated tumor suppressor locus (p16Ink4a and p19Arf) were upregulated in neural stem cells. Deletion of Ink4a or Arf from Bmi-1 -/- mice partially rescued stem cell self-renewal and stem cell frequency well as forebrain proliferation and gut neurogenesis. Arf deficiency, but not Ink4a deficiency, partially rescued cerebellum development, demonstrating regional differences in the sensitivity of progenitors to p16Ink4a and p19Arf. Deletion of both Ink4a and Arf did not affect the growth or survival of Bmi-1-/- mice or completely rescue neural development. Bmi-1 thus prevents the premature senescence of neural stem cells partly via the active repression of negative cell cycle regulators like p16 Ink4a and p19Arf. Overexpression of Bmi-1 in culture and in transgenic mice in vivo demonstrates that Bmi-1 is not only necessary, but also sufficient to promote self-renewal. Ink4a was also upregulated in stem cells during the course of normal aging. This correlated with an age-related depletion of CNS stem cells, as well decreased self-renewal in culture and subventricular zone proliferation in vivo. Deletion of Ink4a alleviated of some of these age-related phenotypes, indicating that the age-related increase in Ink4a expression was partly responsible for the decline in stem cell function and progenitor proliferation in old mice. Our studies of Bmi-1 have provided insight into a highly conserved regulator of stem cell self-renewal and postnatal maintenance. Ultimately, a better understanding of the molecular mechanisms that control the balance between self-renewal and senescence will further increase our understanding of how stem cells persist postnatally and contribute to tissue maintenance throughout adult life, while avoiding neoplastic transformation in old age.PhDBiological SciencesCellular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126513/2/3253357.pd