MeCP2 target genes and Rett syndrome 1571 Fig. 4. Regulation of MeCP2 expression by Bdnf. Post-translational regulation of MeCP2 – MeCP2 is phosphorylated by CaMKII in response to neuron depolarization and Bdnf signaling (Zhou et al., 2006). MeCP2 could also be phosphorylated by other kinases downstream of the Bdnf signaling pathway (dashed lines) resulting in interactions with the 14.3.3 proteins, thus regulating MeCP2 localization and function. Post-transcriptional regulation of MeCP2 – MeCP2’s 3¢ untranslated region contains sites for miR-132, which is activated by CREB. CREB is also downstream of the Bdnf signaling pathway, suggesting the presence of a regulatory loop between Bdnf and MeCP2. AKT, v-akt murine thymoma viral oncogene homolog 1; CAMKK, calcium ⁄ calmodulin-dependent protein kinase kinase; DAG, diacylglycerol; ERK ⁄ MAPK, mitogen activated protein kinase; GAB1, GRB2 associated binder; GRB2, growth factor receptor bound protein 2; IP3, inositol triphosphate; MEK ⁄ MAPKK, mitogen activated protein kinase kinase, PI3K, phosphoinositide-3-kinase; PKC, protein kinase C; PLCc, Phospholipase C gamma 1; Ras, rat sarcoma viral oncogene homolog; RSK, ribosomal protein S6 kinase; SHC, Src homology 2 domain containing transforming protein 1; SOS, son of sevenless. or by modulating cellular distribution of its targets (Mhawech, 2005). The interaction of 14.3.3 proteins with their molecular targets is regulated by phosphorylation events (Deribe et al., 2010). Both AKT- and PKC-mediated phosphorylation of BCL2-associated agonist of cell death (Bad) or v-raf-1 murine leukemia viral oncogene homolog 1 (Raf), among other targets, regulates cell survival and proliferation, respectively. Moreover, cyclin-dependent kinases regulate the cell cycle in part by phosphorylating 14.3.3 partners (Morrison, 2009). Taken together, it is possible that Bdnf prevents MeCP2 transcriptional functions by promoting its interaction with 14.3.3 proteins through a mechanism involving MeCP2 phosphorylation on Ser357 by AKT and ⁄ or on Ser350 and Ser360 by CDKL5, thus favoring neurite outgrowth (Fig. 4). Several of the mutations observed in MeCP2 associated with RTT are located near putative phosphorylation sites – mutation of the Arg110 residue could alter the phosphorylation of Ser113 by PKCa ⁄ b, mutation of Arg294 might affect phosphorylation of Ser292 by PKCe or PKCd, and mutations of Arg168 could impair Ser164 phosphor- ylation by CDKL5 (Fig. 4). This strongly suggests that mutations in MeCP2 found in RTT could impair Bdnf-mediated MeCP2 regulation resulting in abnormal neurite outgrowth. However, it remains to be determined whether MeCP2 is phosphorylated by any of these kinases in response to Bdnf and whether this modulates MeCP2-dependent gene expression. Conclusions Epigenetic regulation of chromatin architecture plays an essential role in brain development and synaptic plasticity, particularly in brain areas related to cognitive and emotional processes. Although the gross anatomy of the brain is largely established at birth, cognitive development during the post-natal period depends upon reorganization in synaptic connectivity driven by sensory experience (Wiesel, 1982). Several neurodevelopmental cognition disorders manifest during this period, suggesting that they might be primarily diseases of synaptic maturation (Zoghbi, 2003). Most major mental illnesses have been proposed to result from multiple risk genes, which supports a stressful environment triggering epigenetic changes in the expression of normal genes (Murgatroyd et al., 2009). Both inherited risk genes as well as abnormalities in epigenetic regulation of normal genes have been implicated in the pathophysiology of many neurodevelopmental or psychiatric disorders. The examples discussed here highlight the importance of methylomics, the regulation of gene expression by methylating DNA and histones, as a key epigenetic mechanism in RTT. Further mechanistic understanding of RTT depends on identifying and validating additional genes responsible for this disorder, specially focusing on the targets that MeCP2 might have on different brain cell types and distinct neuronal phenotypes. Accordingly, a recent study demonstrates that MeCP2 regulates L1 retrotransposition speciﬁcally in neurons (Muotri et al., 2010). These observations provide a new mechanism by which loss of MeCP2 might result in altered gene expression leading to disease. However, additional studies are needed to evaluate the effects of MeCP2 deﬁciency in glial cells as well as at earlier stages of neuronal development, and not just focusing on mature neurons. Also, determining the various levels of cross-talk between different epigenetic mechanisms would help understand the processes leading to RTT and other neurodevelopmental diseases. It would be interesting to determine whether single nucleotide poly- ª 2011 The Authors. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 33, 1563–1574