Retinoic acid-mediated HRas stabilization induces neuronal differentiation of neural stem cells during brain development
Autor: | Kang Yell Choi, Jong Chan Park, Do Sik Min, Woo Jeong Jeong, Mi Yeon Kim |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cellular differentiation Retinoic acid Tretinoin Stimulation Biology Proto-Oncogene Proteins p21(ras) 03 medical and health sciences chemistry.chemical_compound Neural Stem Cells medicine Animals Humans HRAS Molecular Biology Neurons Gene knockdown Protein Stability Vitamin A Deficiency Gene Expression Profiling Neurogenesis Brain Gene Expression Regulation Developmental Cell Differentiation Embryo Cell Biology Embryo Mammalian Neural stem cell Cell biology Mice Inbred C57BL HEK293 Cells 030104 developmental biology medicine.anatomical_structure nervous system chemistry Biochemistry Neuron Developmental Biology medicine.drug |
Zdroj: | Journal of Cell Science. |
ISSN: | 1477-9137 0021-9533 |
Popis: | 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. |
Databáze: | OpenAIRE |
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