P44. Brain tumor suppressors and neural stem cell self-renewal in Drosophila

Abstract

Stem cells are capable of self-renewal and differentiation. Drosophila larval brain neural stem cells, neuroblasts, divide asymmetrically to self-renew and differentiate. Failure of asymmetric cell division can result in their hyperproliferation, a phenotype resembling brain tumors. During asymmetric division of neural stem cells, several proteins controlling the self-renewal vs differentiation decision, including the differentiation factor Numb, are asymmetrically localized and preferentially segregated into one daughter cell. Polo kinase was previously identified as a brain tumor suppressor that mediates the asymmetric localization and segregation of Numb by phosphorylating Pon, an adaptor protein for Numb. We have identified Drosophila Protein Phosphatase 2A (PP2A) as a brain tumor-suppressor that can inhibit self-renewal of neuroblasts. Supernumerary larval brain neuroblasts are generated at the expense of differentiated neurons in PP2A mutants. The PP2A heterotrimeric complex composed of the catalytic subunit (Mts), scaffold subunit (PP2A-29B), and a B regulatory subunit (Tws), is required for the asymmetric cell division of neuroblasts. PP2A complex regulates asymmetric localization of Numb, Pon and atypical protein kinase C as well as proper mitotic spindle orientation. Interestingly, PP2A and Polo kinase enhance Numb and Pon phosphorylation. PP2A, like Polo, acts to prevent excess neuroblast self-renewal primarily by regulating asymmetric localization/activation of Numb. Reduction of PP2A function in larval brains or S2 cells causes a marked decrease in Polo transcript and protein abundance. Overexpression of Polo or Numb significantly suppresses neuroblast overgrowth in PP2A mutants, suggesting that PP2A inhibits excess neuroblast self-renewal in Polo/Numb pathway. We will also discuss about novel players in asymmetric division that we have identified from genetics screens.