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Mecp2 deletion in mouse GABAergic parvalbumin-expressing (PV) cells, cortical interneurons playing a key role in visual experience-induced ocular dominance plasticity, does not result in Rett-like phenotype, other than defects in motor coordination and motor learning. While functions of the visual cortex are preserved in mice lacking Mecp2 in GABAergic PV cells, the visual input-induced spiking responses are decreased. Mecp2 loss impairs maturation of membrane functions of cortical GABAergic PV cells. Mecp2 may be needed for PV cell-mediated cortical GABA inhibition. Mecp2-deficient cortical PV cells show reduced mRNA levels of several genes involved in GABA signaling, such as Parvalbumin, Gad2, Calretinin, Gabra1 and Gabra2, as well as reduced levels of Glu3, a glutamate receptor subunit, and Kv3.1, a potassium channel (He et al. 2014).
Methyl-CpG-binding protein 2 encoded by the MECP2 gene binds to methylated CpG sequences in the DNA. The binding is not generic, however, but is affected by the underlying DNA sequence (Yoon et al. 2003). MECP2 binds to DNA containing 5 methylcytosine (5mC DNA), a DNA modification associated with transcriptional repression (Mellen et al. 2012), both in the context of CpG islands and outside of CpG islands (Chen et al. 2015). In addition, MECP2 binds to DNA containing 5 hydroxymethylcytosine (5hmC DNA), a DNA modification associated with transcriptional activation (Mellen et al. 2012). MECP2 binds to DNA as a monomer, occupying about 11 bp of the DNA. Binding of one MECP2 molecule facilitates binding of the second MECP2 molecule, and therefore clustering can occur at target sites. MECP2 binding to chromatin may be facilitated by nucleosome methylation (Ghosh et al. 2010).
MECP2 was initially proposed to act as a generic repressor of gene transcription. However, high throughput studies of MECP2-induced changes in gene expression in mouse hippocampus (Chahrour et al. 2008), and mouse and human cell lines (Orlic-Milacic et al. 2014) indicate that more genes are up-regulated than down-regulated when MECP2 is overexpressed. At least for some genes directly upregulated by MECP2, it was shown that a complex of MECP2 and CREB1 was involved in transcriptional stimulation (Chahrour et al. 2008, Chen et al. 2013).
MECP2 expression is the highest in postmitotic neurons compared to other cell types, with MECP2 being almost as abundant as core histones. Phosphorylation of MECP2 in response to neuronal activity regulates binding of MECP2 to DNA, suggesting that MECP2 may remodel chromatin in a neuronal activity-dependent manner. The resulting changes in gene expression would then modulate synaptic plasticity and behavior (reviewed by Ebert and Greenberg 2013). In human embryonic stem cell derived Rett syndrome neurons, loss of MECP2 is associated with a significant reduction in transcription of neuronally active genes, as well as the reduction in nascent protein synthesis. The reduction in nascent protein synthesis can at least in part be attributed to the decreased activity of the PI3K/AKT/mTOR signaling pathway. Neuronal morphology (reduced soma size) and the level of protein synthesis in Rett neurons can be ameliorated by treating the cells with growth factors which activate the PI3K/AKT/mTOR cascade or by inhibition of PTEN, the negative regulator of AKT activation. Mitochondrial gene expression is also downregulated in Rett neurons, which is associated with a reduced capacity of the mitochondrial electron transport chain (Ricciardi et al. 2011, Li et al. 2013). Treatment of Mecp2 null mice with IGF1 (insulin-like growth factor 1) reverses or ameliorates some Rett-like features such as locomotion, respiratory difficulties and irregular heart rate (Tropea et al. 2009).
MECP2 regulates expression of a number of ligands and receptors involved in neuronal development and function. Ligands regulated by MECP2 include BDNF (reviewed by Li and Pozzo-Miller 2014, and KhorshidAhmad et al. 2016), CRH (McGill et al. 2006, Samaco et al. 2012), SST (Somatostatin) (Chahrour et al. 2008), and DLL1 (Li et al. 2014). MECP2 also regulates transcription of genes involved in the synthesis of the neurotransmitter GABA – GAD1 (Chao et al. 2010) and GAD2 (Chao et al. 2010, He et al. 2014). MECP2 may be involved in direct stimulation of transcription from the GLUD1 gene promoter, encoding mitochondrial glutamate dehydrogenase 1, which may be involved in the turnover of the neurotransmitter glutamate (Livide et al. 2015). Receptors regulated by MECP2 include glutamate receptor GRIA2 (Qiu et al. 2012), NMDA receptor subunits GRIN2A (Durand et al. 2012) and GRIN2B (Lee et al. 2008), opioid receptors OPRK1 (Chahrour et al. 2008) and OPRM1 (Hwang et al. 2009, Hwang et al. 2010, Samaco et al. 2012), GPRIN1 (Chahrour et al. 2008), MET (Plummer et al. 2013), NOTCH1 (Li et al. 2014). Channels/transporters regulated by MECP2 include TRPC3 (Li et al. 2012) and SLC2A3 (Chen et al. 2013). MECP2 regulates transcription of FKBP5, involved in trafficking of glucocorticoid receptors (Nuber et al. 2005, Urdinguio et al. 2008). MECP2 is implicated in regulation of expression of SEMA3F (semaphorin 3F) in mouse olfactory neurons (Degano et al. 2009). In zebrafish, Mecp2 is implicated in sensory axon guidance by direct stimulation of transcription of Sema5b and Robo2 (Leong et al. 2015). MECP2 may indirectly regulate signaling by neuronal receptor tyrosine kinases by regulating transcription of protein tyrosine phosphatases, PTPN1 (Krishnan et al. 2015) and PTPN4 (Williamson et al. 2015).
MECP2 regulates transcription of several transcription factors involved in functioning of the nervous system, such as CREB1, MEF2C, RBFOX1 (Chahrour et al. 2008) and PPARG (Mann et al. 2010, Joss-Moore et al. 2011).
MECP2 associates with transcription and chromatin remodeling factors, such as CREB1 (Chahrour et al. 2008, Chen et al. 2013), the HDAC1/2-containing SIN3A co-repressor complex (Nan et al. 1998), and the NCoR/SMRT complex (Lyst et al. 2013, Ebert et al. 2013). There are contradictory reports on the interaction of MECP2 with the SWI/SNF chromatin-remodeling complex (Harikrishnan et al. 2005, Hu et al. 2006). Interaction of MECP2 with the DNA methyltransferase DNMT1 has been reported, with a concomitant increase in enzymatic activity of DNMT1 (Kimura and Shiota 2003).
In addition to DNA binding-dependent regulation of gene expression by MECP2, MECP2 may influence gene expression by interaction with components of the DROSHA microprocessor complex and the consequent change in the levels of mature microRNAs (Cheng et al. 2014, Tsujimura et al. 2015).
Increased MECP2 promoter methylation is observed in both male and female autism patients (Nagarajan et al. 2008). Regulatory elements that undergo methylation are found in the promoter and the first intron of MECP2 and their methylation was shown to regulate Mecp2 expression in mice (Liyanage et al. 2013). Mouse Mecp2 promoter methylation was shown to be affected by stress (Franklin et al. 2010).
The Rett-like phenotype of Mecp2 null mice is reversible (Guy et al. 2007), but appropriate levels of Mecp2 expression need to be achieved (Alvarez-Saavedra et al. 2007). When Mecp2 expression is restored in astrocytes of Mecp2 null mice, amelioration of Rett symptoms occurs, involving non-cell-autonomous positive effect on mutant neurons and increasing level of the excitatory glutamate transporter VGLUT1 (Lioy et al. 2011). Microglia derived from Mecp2 null mice releases higher than normal levels of glutamate, which has toxic effect on neurons. Increased glutamate secretion may be due to increased levels of glutaminase (Gls), involved in glutamate synthesis, and increased levels of connexin-32 (Gjb1), involved in glutamate release, in Mecp2 null microglia (Maezawa and Jin 2010). Targeted deletion of Mecp2 from Sim1-expressing neurons of the mouse hypothalamus recapitulates some Rett syndrome-like features and highlights the role of Mecp2 in feeding behavior and response to stress (Fyffe et al. 2008).
Mecp2 overexpression, similar to MECP2 duplication syndrome, causes neurologic phenotype similar to Rett (Collins et al. 2004, Luikenhuis et al. 2004, Van Esch et al. 2005, Alvarez-Saavedra 2007, Van Esch et al. 2012). The phenotype of the mouse model of the MECP2 duplication syndrome in adult mice is reversible when Mecp2 expression levels are corrected (Sztainberg et al. 2015).