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.

▪ Abstract O₂sensing is a fundamental biological process necessary for adaptation of living organisms to variable habitats and physiological situations. Cellular responses to hypoxia can be acute or chronic. Acute responses rely mainly on O₂-regulated ion channels, which mediate adaptive changes in cell excitability, contractility, and secretory activity. Chronic responses depend on the modulation of hypoxia-inducible transcription factors, which determine the expression of numerous genes encoding enzymes, transporters and growth factors. O₂-regulated ion channels and transcription factors are part of a widely operating signaling system that helps provide sufficient O₂to the tissues and protect the cells against damage due to O₂deficiency. Despite recent advances in the molecular characterization of O₂-regulated ion channels and hypoxia-inducible factors, several unanswered questions remain regarding the nature of the O₂sensor molecules and the mechanisms of interaction between the sensors and the effectors. Current models of O₂sensing are based on either a heme protein capable of reversibly binding O₂or the production of oxygen reactive species by NAD(P)H oxidases and mitochondria. Complete molecular characterization of the hypoxia signaling pathways will help elucidate the differential sensitivity to hypoxia of the various cell types and the gradation of the cellular responses to variable levels of PO₂. A deeper understanding of the cellular mechanisms of O₂sensing will facilitate the development of new pharmacological tools effective in the treatment of diseases such as stroke or myocardial ischemia caused by localized deficits of O₂.