title: MicroRNA-34a Modulates Neural Stem Cell Differentiation by Regulating Expression of Synaptic and Autophagic Proteins.
abstract: 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.
authors: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003, Lisbon, Portugal.
authors: Ana L
authors: AL
authors: Morgado
authors: Joana M
authors: JM
authors: Xavier
authors: Pedro A
authors: PA
authors: Dionísio
authors: Maria F C
authors: MF
authors: Ribeiro
authors: Raquel B
authors: RB
authors: Dias
authors: Ana M
authors: AM
authors: Sebastião
authors: Susana
authors: S
authors: Solá
authors: Cecília M P
authors: CM
authors: Rodrigues
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D000071183:Autophagy-Related Proteins; D002454:Cell Differentiation / Q000502:physiology*; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D058953:Neural Stem Cells / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D050863:Synaptotagmin I / Q000096:biosynthesis*; D033921:Vesicular Transport Proteins / Q000096:biosynthesis*
chemical_list: C549015:Atg9A protein, mouse; D000071183:Autophagy-Related Proteins; C551848:MIRN34a microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; D033921:Vesicular Transport Proteins