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Continual generation of new neural cells from adult neural stem/progenitor cells (NPCs) is an important component of life‐long brain plasticity. However, the intrinsic regulation of this process remains poorly defined. Here we report that Wip1 phosphatase, previously studied in oncogenesis, functions as a crucial physiological regulator in adult neural cell generation. Wip1 deficiency resulted in a 90% decrease in new cell formation in adult olfactory bulb, accompanied by aberrantly decreased NPC amplification, stem cell frequency, and self‐renewal. At a cellular level, Wip1 knockout NPCs exhibit a prolonged cell cycle, an accumulation at G 2  to M phase transition, and enhanced p53 activity. Interestingly, the impaired M‐phase entry and NPC amplification of Wip1‐null mice can be reversed in Wip1/p53 double‐null mice. Importantly, there is no difference in NPC amplification between p53‐null and Wip1/p53 double‐null mice. Our data demonstrate that Wip1 regulates the generation of new neural cells in adult olfactory bulb specifically through p53‐dependent M‐phase entry of the NPC cell cycle. S TEM  C ELLS  2009;27:1433–1442

Wip1 Regulates the Generation of New Neural Cells in the Adult Olfactory Bulb through p53‐Dependent Cell Cycle Control