European Journal of Neuroscience European Journal of Neuroscience, Vol. 33, pp. 1563–1574, 2011 doi:10.1111/j.1460-9568.2011.07658.x REVIEW In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system Sol Dı´ az de Leo´ n-Guerrero, Gustavo Pedraza-Alva and Leonor Pe´ rez-Mart´ınez Laboratorio de Neuroinmunobiolog´ıa, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnolog´ıa, Universidad Nacional Auto´ noma de Me´ xico, A.P. 510-3, Cuernavaca, Morelos 62271, Me´ xico Keywords: chromatin remodeling, epigenetics, mental retardation, microRNAs, Rett syndrome, signal transduction neurodevelopmental disorders Abstract The array of specialized neuronal and glial cell types that characterize the adult central nervous system originates from neuroepithelial proliferating precursor cells. The transition from proliferating neuroepithelial precursor cells to neuronal lineages is accompanied by rapid global changes in gene expression in coordination with epigenetic modiﬁcations at the level of the chromatin structure. A number of genetic studies have begun to reveal how epigenetic deregulation results in neurodevelopmental disorders such as mental retardation, autism, Rubinstein–Taybi syndrome and Rett syndrome. In this review we focus on the role of the methyl- CpG binding protein 2 (MeCP2) during development of the central nervous system and its involvement in Rett syndrome. First, we present recent ﬁndings that indicate a previously unconsidered role of glial cells in the development of Rett syndrome. Next, we discuss evidence of how MeCP2 deﬁciency or loss of function results in aberrant gene expression leading to Rett syndrome. We also discuss MeCP2’s function as a repressor and activator of gene expression and the role of its different target genes, including microRNAs, during neuronal development. Finally, we address different signaling pathways that regulate MeCP2 expression at both the post-transcriptional and post-translational level, and discuss how mutations in MeCP2 may result in lack of responsiveness to environmental signals. Introduction Understanding the molecular mechanisms that control the phenotypic identity of distinct neuronal classes at deﬁned regions within the central nervous system constitutes a widely relevant issue in developmental neuroscience. Neurons permanently exit the cell cycle and remain quiescent. Neuronal mitotic quiescence is crucial for the maintenance of the complexly wired brain. Therefore, neuronal differentiation encompasses an elaborate developmental program in which neurogenic and antiproliferative signals work in concert to ensure the differentiated state (Perez-Martinez & Jaworski, 2005). During development, mitotically active precursors located within the neuroepithelium give rise to all the neuronal and glial cells of the brain. Recent genetic studies in vertebrate and invertebrate models have shown that neuronal differentiation is under the control of complex regulatory networks of transcription factors, which are activated in response to inductive signals. The coordinated actions of these proteins direct neuronal fate identity in appropriate spatial and temporal contexts during central nervous system development (Jurata et al., 2000; Lee & Pfaff, 2001; Fig. 1). Correspondence: Leonor Pe´rez-Mart´ınez, as above. E-mail: leonor@ibt.unam.mx Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms Received 28 November 2010, revised 27 January 2011, accepted 16 February 2011 Environmental cues, via speciﬁc intracellular signaling pathways, control neuronal differentiation at multiple levels: neuronal precursor cell cycle control, migration, synaptogenesis, neuronal survival and neurotransmitter phenotype. As mentioned above, these cellular responses result from the induction of timely coordinated cascades of gene expression controlled by speciﬁc and ubiquitous transcription factors. These transcription factors in turn induce either the expression of structural genes required for speciﬁc functions of a given neuronal lineage and ⁄ or the expression of non-coding RNAs that play an important regulatory role. Among the small non-coding RNAs identiﬁed so far are those with (i) gene-silencing effects [small interfering RNAs (siRNAs) and microRNAs (miRNAs)] at the post- transcriptional level and (ii) small modulatory double-strand RNAs (smRNAs) that regulate gene expression at the transcriptional level through double-stranded RNA ⁄ protein interactions (Mattick & Makunin, 2005). In mammals, certain miRNAs have been implicated as important regulators in the maintenance of the pluripotent cell state during early development (Houbaviy et al., 2003) and neurogenesis (Sempere et al., 2004). However, recent studies have demonstrated that the action of transcription factors mediating neuronal differentiation depends on speciﬁc epigenetic traits like histone post-translational modiﬁcations, polyADP-ribosylation and DNA methylation. Here, we review the latest studies aimed at understanding how an epigenetic deregulation results in neurodevelopmental disorders. Speciﬁcally, we focus on the role of the methyl-CpG binding protein 2 (MeCP2) in neuronal development and disease. We also discuss different MeCP2 targets including miRNAs, and mechanisms of MeCP2 regulation. ª 2011 The Authors. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd