conﬁrmed as MeCP2 targets in the central nervous system: the brain- derived neurotrophic factor (Bdnf) and distal-les homeobox 5 (dlx5), which is on an imprinted region in chromosome 7 (reviewed in Chadwick & Wade, 2007). MeCP2 regulates Bdnf expression by binding to the promoter IV and repressing its transcription. This repression can be relieved by neuronal depolarization, which triggers Ca2+-dependent phosphorylation of MeCP2 and subsequent dissoci- ation of MeCP2 from the Bdnf promoter IV, leading to increased Bdnf transcription (Chen et al., 2003; Zhou et al., 2006). However, contrary to what was expected, patients with RTT as well as mouse models of RTT show lower levels of Bdnf compared with healthy individuals and WT animals, respectively (Chang et al., 2006). Many studies have been performed to elucidate how MeCP2 regulates Bdnf expression (Chen et al., 2003; Wang et al., 2006; Zhou et al., 2006), which is key to understanding RTT as most of the RTT phenotypes can be attributed to a deregulation of Bdnf expression in the brain (Chang et al., 2006; Table 2). Accordingly, Bdnf overexpression rescues the morphology of MeCP2-deﬁcient neurons (Larimore et al., 2009). Another study suggests that Bdnf downregulation in MeCP2-deﬁcient mice may be mediated by repressor and co-repressor molecules like REST and CoREST (Abuhatzira et al., 2007). MeCP2 is able to repress both REST and CoREST, which correlate with an overexpression of these two factors in MeCP2-deﬁcient brain. REST and CoREST can bind between Bdnf promoters I and II, and repress Bdnf transcription. Thus, in the absence of MeCP2, Bdnf transcription is mainly regulated by REST ⁄ CoREST, which do not respond to neuronal activity, resulting in lower levels of Bdnf. In WT mice, MeCP2 binds to promoter IV of Bdnf and mediates neuronal activity-dependent transcription of Bdnf. Deregulation of REST ⁄ CoREST could also help to explain the expression pattern of other genes that have been found to be downregulated in MeCP2-deﬁcient brains (Nomura et al., 2008). Table 2. Regulation of Bdnf by MeCP2 Mechanism In the absence of neural activity, MeCP2 binds to Bdnf promoter IV and represses Bdnf expression Membrane depolarization causes calcium-dependent MeCP2 phosphorylation and subsequent release from Bdnf promoter IV Loss of MeCP2 affects Bdnf secretion Receptor of activated protein kinase C1 (Rack1) is able to dissociate MeCP2 from Bdnf promoter IV, leading to Bdnf activation MeCP2-deﬁcient brain presents lower levels of Bdnf MeCP2 deﬁciency increases the expression of both REST and CoREST, which in turn downregulate Bdnf levels by binding between Bdnf promoters I and II Reference(s) Chen et al. (2003) Zhou et al. (2006) Wang et al. (2006) He et al. (2010) Abuhatzira et al. (2007) Abuhatzira et al. (2007)) Reference(s) See Table 2 Horike et al. (2005) Szulwach et al. (2010) Nomura et al. (2008) Liu et al. (2010) Abuhatzira et al. (2007) Chahrour et al. (2008) MeCP2 target genes and Rett syndrome 1567 In addition to its well-accepted role as a transcriptional repressor, a considerable amount of data suggests a role for MeCP2 as a transcriptional activator (Chahrour et al., 2008; Ben-Shachar et al., 2009; Urdinguio et al., 2010). Given that some of the phenotypes associated with RTT could be attributed to hypothalamic dysfunction, Chahrour et al. (2008) deﬁned the hypothalamic gene proﬁle of WT, MeCP2-null and MeCP2-overexpressing (MeCP2-tg) mice using microarray screening. This study identiﬁed 2582 genes that were misregulated in both MeCP2-tg and MeCP2-null mice. The authors identiﬁed 2148 genes that were upregulated in the MeCP2-tg mice and downregulated in the mice, and only 377 that were downregulated in MeCP2-tg mice and upregulated in mice. Among these genes are different neurotransmitters (e.g. corticotropin-releasing hormone and somatostatin) and neurotransmitter receptors (e.g. thyroid hor- mone receptor alpha and thyrotropin-releasing hormone receptor) that could help to explain the hypothalamic dysfunction. Also of note are different genes coding for regulatory proteins like Bdnf, reelin, cAMP responsibe element binding protein 1 (Creb1) and Creb3, as well as chromatin remodelers like different HDACs and transformation/ transcription domain-associated protein (Trapp), the latter being previously identiﬁed as an enriched transcript in the hypothalamus (Guerra-Crespo et al., 2011; Table 3). Most of these genes were found to be upregulated by MeCP2, whereas only reelin and HDAC9 were found to be repressed by MeCP2. This shows that in the hypothalamus the majority of genes targeted by MeCP2 are positively regulated, which clashes with the idea of MeCP2 being primarily a repressor. However, bisulﬁte sequencing showed that genes repressed by MeCP2 presented a higher degree of methylation than genes activated by MeCP2. The fact that MeCP2 binds preferentially to methylated DNA (Skene et al., 2010) suggests that, to promote gene expression, MeCP2 could be acting through another protein to bind and to activate Model Rat hippocampal neurons Adult MeCP2-null mice (MeCP2) ⁄ y) SH-SY5Y human neuroblastoma cells MeCP2-deﬁcient human and mouse brains MeCP2-deﬁcient human and mouse brains Table 3. MeCP2 targets and their function Targets Bdnf Dlx5 miR-137 miR-184 REST In the hypothalamus Function Essential for neuronal survival, differentiation, synaptic plasticity and dendrite outgrowth Imprinted gene, homeobox transcription factor, regulates the enzymes that synthesize GABA Role in differentiation and proliferation, inhibits Ezh2 Role in differentiation and proliferation Repression of neurogenic genes Chromatin remodelers – HDACs and Trapp Neurotransmitters – Crh and Ssh Receptors – Trhr and Thra Crh, corticotropin-releasing hormone; Dlx5, distal-les homeobox 5; Ssh, somatostatin; Trhr, thyrotropin-releasing hormone receptor; Thra, thyroid hormone receptor alpha; Trapp, transformation ⁄ transcription domain-associated protein. 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