title: Retinoic-acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development.
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-acid-supplemented 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.
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Jong-Chan
authors.initials: JC
authors.lastname: Park
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Jeong
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan 609-735, Korea.
authors.forename: DoSik
authors.initials: D
authors.lastname: Min
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea kychoi@yonsei.ac.kr.
authors.forename: Kang-Yell
authors.identifier: 0000-0002-0952-3276
authors.initials: KY
authors.lastname: Choi
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000473:pathology
chemical_list: D014212:Tretinoin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HRas; Neural stem cell; Neuronal differentiation; Retinoic acid; Vitamin A deficiency