[P59]: C‐myc increases stemness of neural progenitor cells

Activation of endogenous neural precursors for therapeutic regeneration is limited by their low numbers. Identifying genes that regulate population size, therefore, is integral to maximizing their potential. We have shown that p107 negatively controls both the number of neural precursors and their capacity for self-renewal. The mechanism whereby p107 regulates neural precursor self-renewal has not yet been determined. Since the Notch-Hes signaling pathway is necessary for neural stem cell self-renewal and p107 deficient mice exhibit enhanced expression of Notch1 and Hes1; we questioned whether this pathway is responsible for the increased neural precursor population in p107 null mice. To address these questions, we interbred p107 and Hes1 deficient mice to generate double null mutants. Loss of Hes1 in p107 null embryos restored the number of neural precursors to wild type levels. In adult p107 mutants, loss of a single Hes1 allele reduced the number of progenitor cells demonstrating that the Notch-Hes pathway also regulates this population in the adult animal. Deregulation of Hes1, therefore accounts for the enhanced numbers of neural precursors in both embryonic and adult p107 null mice. Luciferase reporter assays demonstrated robust repression of Hes1 promotor activity by p107. These results reveal an interaction between the cell cycle inhibitor, p107, and the Notch-Hes signaling pathway that directly impacts neural precursor numbers. In summary, we show a novel mechanism for p107, whereby repressing Hes1, p107 not only negatively regulates neural precursor self-renewal but also promotes differentiation.