Retinoic-acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development

Jong Chan Park, Woo Jeong Jeong, Mi Yeon Kim, Do Sik Min, Kang Yell Choi

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10 Citations (Scopus)

Abstract

Ras signaling is tightly regulated during neural stem cell (NSC) differentiation, and defects in this pathway result in aberrant brain development. However, the mechanism regulating Ras signaling during NSC differentiation was unknown. Here, we show that stabilized HRas specifically induces neuronal differentiation of NSCs. Lentivirus-mediated HRas overexpression and knockdown resulted in stimulation and inhibition, respectively, of NSC differentiation into neuron in the ex vivo embryo. Retinoic acid, an active metabolite of vitamin A, promoted neuronal differentiation of NSCs by stabilizing HRas, and HRas knockdown blocked the retinoic acid effect. Vitamin-A-deficient mice displayed abnormal brain development with reduced HRas levels and a reduced thickness of the postmitotic region containing differentiated neurons. All of these abnormal phenotypes were rescued with the restoration of HRas protein levels achieved upon feeding with a retinoic-acidsupplemented diet. In summary, this study shows that retinoic acid stabilizes HRas protein during neurogenesis, and that this is required for NSC differentiation into neurons and murine brain development.

Original languageEnglish
Pages (from-to)2997-3007
Number of pages11
JournalJournal of cell science
Volume129
Issue number15
DOIs
Publication statusPublished - 2016 Jan 1

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All Science Journal Classification (ASJC) codes

  • Cell Biology

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