The existence of stem cells in the adult mammalian central nervous system (CNS) suggests that the brain is capable of regeneration and repair, yet the mechanisms that regulate stem cell self-renewal and the generation of new neurons are poorly understood. The oncogene bmi1 promotes the self-renewal of CNS stem cells in part by repressing the cell cycle regulator p16ink4a. Mice lacking Bmi1 experience progressive gait disturbances and postnatal depletion of forebrain stem cells. To better understand the role of Bmil in neurogenesis and stem cell self-renewal three specific aims are proposed: First, to characterize the effects of Bmi1 deficiency on adult olfactory bulb neurogenesis by quantifying neurogenesis in Bmi1 deficient mice. Secondly, to determine if the depletion of postnatal stem cells in Bmi1 deficient mice is mediated by the tumor suppressor p16ink4a. Finally, to overexpress Bmi1 in forebrain stem cells in order to determine whether Bmi1 is sufficient to promote stem cell self-renewal. In sum, the goal of these aims is explore a model system in which stem cells are depleted in order to understand the normal role of stem cells in building and regenerating the adult mammalian brain.
|Molofsky, Anna V; He, Shenghui; Bydon, Mohammad et al. (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19:1432-7|
|Pardal, R; Molofsky, A V; He, S et al. (2005) Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol 70:177-85|