Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control.
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.
Zhu
Yun-Hua
YH
Department of Clinical Research, Singapore General Hospital, Singapore.
Zhang
Cheng-Wu
CW
Lu
Li
L
Demidov
Oleg N
ON
Sun
Li
L
Yang
Lan
L
Bulavin
Dmitry V
DV
Xiao
Zhi-Cheng
ZC
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation / Q000235:genetics; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C