An increase in MECP2 dosage impairs neural tube formation

Epigenetic mechanisms are fundamental for shaping the activity of the central nervous system (CNS). Methyl-CpG binding protein 2 (MECP2) acts as a bridge between methylated DNA and transcriptional effectors responsible for differentiation programs in neurons. The importance of MECP2 dosage in CNS is evident in Rett Syndrome and MECP2 duplication syndrome, which are neurodevelopmental diseases caused by loss-of-function mutations or duplication of the MECP2 gene, respectively. Although many studies have been performed on Rett syndrome models, little is known about the effects of an increase in MECP2 dosage. Herein, we demonstrate that MECP2 overexpression affects neural tube formation, leading to a decrease in neuroblast proliferation in the neural tube ventricular zone. Furthermore, an increase in MECP2 dose provokes premature differentiation of neural precursors accompanied by greater cell death, resulting in a loss of neuronal populations. Overall, our data indicate that correct MECP2 expression levels are required for proper nervous system development. © 2014 .This study was supported by the European Community's Seventh Framework Program (FP7/2007–2013), under grant agreement PITN-GA-2009-238242 and the project DISCHROM; ERC with grant agreement 268626; the project EPINORC; the E-RARE EuroRETT network (Carlos II Health Institute project PI071327); the Fondation Lejeune (France); MINECO projects SAF2011-22803, CSD2006-00049, BFU2009-11527 and BFU-2012-34261; Grant 090210 from Fundaciò La Marató de TV3; the Cellex Foundation; the Botín Foundation; the Catalan Association for Rett Syndrome; and the Health and Science Departments of the Catalan government (Generalitat de Catalunya). NA and CE received an I3P fellowship (I3P-BPD2005) and FPU fellowships respectively. ME is an ICREA Research ProfessorPeer Reviewe