PhD Gradute: ZHU Yunhua
Thesis Title: Wip1 regulates proliferation of adult neural progenitors through p53-dependent G2 phase cell cycle control
The activity of Neural Stem/Progenitor Cells (NPCs) declines with aging, however the intrinsic regulators of this process are poorly defined. Here we report that Wip1 phosphatase functions as a critical physiological regulator of adult neurogenesis and potentially operates as an important mechanism of aging-induced decline in proliferation of NPCs.
In adult olfactory bulb, a Wip1 deficiency results in a 90% decrease in new cells formation, accompanied by decreased amplification of NPCs of sub-ventricular zone, reduced stem cell frequency and self-renewal. Similarly, adult neurogenesis in hippocampus is also diminished upon knocking out Wip1. At cellular level, Wip1 deficient NPCs exhibit a prolonged cell cycle, an accumulation at G2 to M phase and elevated expression of G2 phase inhibitors. The impaired M-phase entry and reduced proliferation of Wip1 deficient NPCs are both reversed in Wip1/p53 double deficient mice. The functional rescue in a p53 deficient background was also observed in vivo in the number of NPCs and neuroblasts. Thus, Wip1 regulates the generation of new neural cells in adult olfactory bulb through a p53-dependent control of cell cycle progression.
In turn, during aging, the number of NPCs was reduced, which correlated with a marked down-regulation of Wip1 and a drastic up-regulation of p53 phosphorylation. Our results propose the important function of Wip1/p53 pathway in adult neurogenesis with possibly of regulation of NPCs aging.
Ref: Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control. Stem Cells. 2009 Jun;27(6):1433-42.PMID: 19489034
A: Proliferation of neural progenitors decreases during aging
B: Complete reduction (ko) of Wip1 cause reduction in the proliferation of neural progenitors
C: Wip1 expression reduces during aging of neural progenitors
D: Transgenic expression of Wip1 in aged NPC promotes proliferation
E: In young neural progenitors, Wip1 is abundantly expressed and represses the activity of p53 to promote cell cycle progress.
F: In old animals, expression of Wip1 is reduced, at the same time, positive regulation by accumulated DNA damage and telomere shortening increases. Therefore p53 activity rises to a high level. The activation of p53, together with the rise of p16Ink4a, restricts cell cycle progression, self-renewal as well as neuronal differentiation.
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