MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling
Feldman, Danielle A.
Sheridan, Steven D.
Ip, Jacque P.K.
Amoah, Stephen K.
Rodriguez, Brian A.
Sur, MrigankaNote: Order does not necessarily reflect citation order of authors.
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CitationMellios, 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.
AbstractRett 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.
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