Neuronal NOS Induces Neuronal Differentiation Through a PKCα-Dependent GSK3β Inactivation Pathway in Hippocampal Neural Progenitor Cells

Shin Young Park, Min Jeong Kang, Joong Soo Han

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

We investigated the role of neuronal nitric oxide synthase (nNOS) in the neuronal differentiation of neural progenitor cells (NPCs) from hippocampi of E16.5 rat embryos. The production of nitric oxide (NO) and nNOS expression increased markedly during neuronal differentiation as did the expression of neurotrophin-3 (NT3), neurotrophin-4/5 (NT 4/5), and synapsin I. nNOS siRNA or the nNOS inhibitor, 7-nitroindazole (7-NI), decreased expression of the neurotrophins and synapsin I, and suppressed neurite outgrowth. These results suggest that nNOS plays a critical role in neuronal differentiation of hippocampal NPCs. nNOS-mediated neuronal differentiation is controlled by calcineurin since cyclosporin A (CsA), a calcineurin inhibitor, decreased nNOS activation and NO production, and inhibited neurite outgrowth. We found that inactivation of glycogen synthase kinase-3 beta (GSK3β) resulting from activation of protein kinase C alpha (PKCα) is involved in the nNOS-mediated neuronal differentiation. Moreover, lithium chloride (LiCl), a GSK3β inhibitor, increased neuronal differentiation by inhibiting the proliferation of NPCs. Taken together, these results suggest that neuronal differentiation is dependent on calcineurin-mediated activation of nNOS; this induces PKCα-dependent inactivation of GSK3β, which leads to inhibition of the proliferation of hippocampal NPCs.

Original languageEnglish
Pages (from-to)5646-5656
Number of pages11
JournalMolecular Neurobiology
Volume54
Issue number7
DOIs
StatePublished - 2017 Sep 1

Keywords

  • Cyclosporin A
  • GSK3β
  • Hippocampal neural progenitor cells
  • NO
  • PKCα
  • nNOS

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