Molecular Neurobiology

, Volume 56, Issue 3, pp 1946–1956 | Cite as

Possible Involvement of PI3-K/Akt-Dependent GSK-3β Signaling in Proliferation of Neural Progenitor Cells After Hypoxic Exposure

  • Keishi Kisoh
  • Hideki Hayashi
  • Miho Arai
  • Maiko Orita
  • Bo Yuan
  • Norio TakagiEmail author


We previously demonstrated that proliferation of endogenous neural progenitor cells is enhanced by cerebral ischemia and that phosphatidylinositol 3-kinase (PI3-K)/Akt-dependent glycogen synthase kinase (GSK)-3β signaling is involved in ischemia-induced neurogenesis. It is important to learn more about the regulation of proliferation and differentiation of neural progenitor cells under ischemic conditions, as such knowledge that may serve as the basis for the development of new therapeutic approaches for stroke. However, it remains to be addressed whether a change in that signaling pathway is induced in neural progenitor cells. We prepared neural progenitor cells by using the neurosphere method and conducted experiments to determine the relative contributions of the PI3-K/Akt-dependent GSK-3β signaling pathway to the proliferation and differentiation of neural progenitor cells under the hypoxic condition in vitro. We showed that hypoxic exposure induced the proliferation of neural progenitor cells. This proliferation was accompanied by phosphorylation of Akt and GSK-3β at its Ser9. Furthermore, treatment with a PI3-K inhibitor decreased the hypoxia-induced phosphorylation of GSK-3β and proliferation of neural progenitor cells. Furthermore, hypoxic exposure enhanced the differentiation of neural progenitor cells, and this increased differentiation was not affected by treatment with the PI3-K inhibitor. Although the expression of NeuroD1 mRNA during cell differentiation was also enhanced by hypoxic exposure, this increased expression was not affected by treatment with the PI3-K inhibitor. Our findings suggest that the PI3K/Akt-dependent GSK-3β signaling pathway was involved in the proliferation of neural progenitor cells under a pathologic condition, such as hypoxia and/or cerebral ischemia in vivo.


Cerebral ischemia Neural progenitor cell Neurogenesis GSK-3β PI3-K/Akt Hypoxia 



Glycogen synthase kinase


Phosphatidylinositol 3-kinase


Sub-granular zone


Funding Information

This research was supported in part by the Takeda Science Foundation.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.


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Authors and Affiliations

  1. 1.Department of Applied BiochemistryTokyo University of Pharmacy and Life SciencesTokyoJapan

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