Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16^Ink4a and p19 ^Arf senescence pathways

Bmi-1 is required for the post-natal maintenance of stem cells in multiple tissues including the central nervous system (CNS) and peripheral nervous system (PNS). Deletion of Ink4a or Arf from Bmi-1^-/- mice partially rescued stem cell self-renewal and stem cell frequency in the CNS and PNS, as 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 p16^Ink4a and p19^Arf. 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 by repressing Ink4a and Arf, but additional pathways must also function downstream of Bmi-1.