MicroRNA-34a Modulates Neural Stem Cell Differentiation by Regulating Expression of Synaptic and Autophagic Proteins

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• 作者：Ana L. Morgado ; Joana M. Xavier ; Pedro A. Dionísio…
• 关键词：Autophagy ; MicroRNA ; Neural stem cell ; Neurogenesis ; Synaptogenesis
• 刊名：Molecular Neurobiology
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：51
• 期：3
• 页码：1168-1183
• 全文大小：3,368 KB
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• 作者单位：Ana L. Morgado (1)
  Joana M. Xavier (1)
  Pedro A. Dionísio (1)
  Maria F. C. Ribeiro (1)
  Raquel B. Dias (3) (4)
  Ana M. Sebasti?o (3) (4)
  Susana Solá (1) (2)
  Cecília M. P. Rodrigues (1) (2)
  
  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal
  3. Faculty of Medicine, Institute of Pharmacology and Neurosciences, Universidade de Lisboa, Lisbon, Portugal
  4. Unit of Neurosciences, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal
  2. Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

We have previously demonstrated the involvement of specific apoptosis-associated microRNAs (miRNAs), including miR-34a, in mouse neural stem cell (NSC) differentiation. In addition, a growing body of evidence points to a critical role for autophagy during neuronal differentiation, as a response-survival mechanism to limit oxidative stress and regulate synaptogenesis associated with this process. The aim of this study was to further investigate the precise role of miR-34a during NSC differentiation. Our results showed that miR-34a expression was markedly downregulated during neurogenesis. Neuronal differentiation and cell morphology, synapse function, and electrophysiological maturation were significantly impaired in miR-34a-overexpressing NSCs. In addition, synaptotagmin 1 (Syt1) and autophagy-related 9a (Atg9a) significantly increased during neurogenesis. Pharmacological inhibition of autophagy impaired both neuronal differentiation and cell morphology. Notably, we showed that Syt1 and Atg9a are miR-34a targets in neural differentiation context, markedly decreasing after miR-34a overexpression. Syt1 overexpression and rapamycin-induced autophagy partially rescued the impairment of neuronal differentiation by miR-34a. In conclusion, our results demonstrate a novel role for miR-34a regulation of NSC differentiation, where miR-34a downregulation and subsequent increase of Syt1 and Atg9a appear to be crucial for neurogenesis progression.