MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling

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MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling

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Title: MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling
Author: Mellios, Nikolaos; Feldman, Danielle A.; Sheridan, Steven D.; Ip, Jacque P.K.; Kwok, Showming; Amoah, Stephen K.; Rosen, Bess; Rodriguez, Brian A.; Crawford, Benjamin; Swaminathan, Radha; Chou, Stephanie; Li, Yun; Ziats, Mark; Ernst, Carl; Jaenisch, Rudolf; Haggarty, Stephen J.; Sur, Mriganka

Note: Order does not necessarily reflect citation order of authors.

Citation: Mellios, N., D. A. Feldman, S. D. Sheridan, J. P. Ip, S. Kwok, S. K. Amoah, B. Rosen, et al. 2018. “MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling.” Molecular psychiatry :10.1038/mp.2017.86. doi:10.1038/mp.2017.86. http://dx.doi.org/10.1038/mp.2017.86.
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Abstract: Rett Syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the Methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. While postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of miRNAs in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 shRNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK/MAPK) and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and 3D (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors (NPs) deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in WT mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.
Published Version: doi:10.1038/mp.2017.86
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815944/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:35014915
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