Search results for GAD1

Showing 13 results out of 13

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Protein (2 results from a total of 2)

Identifier: R-HSA-888580
Species: Homo sapiens
Compartment: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
Primary external reference: UniProt: GAD1: Q99259
Identifier: R-HSA-947477
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: Q99259

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-9022972
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSG00000128683

Reaction (3 results from a total of 3)

Identifier: R-HSA-9022935
Species: Homo sapiens
Compartment: nucleoplasm
Based on studies in mice, MECP2 directly binds the promoter region of the GAD1 (GAD67) gene, encoding glutamate decarboxylase 1, an enzyme involved in GABA synthesis (Chao et al. 2010).
Identifier: R-HSA-9022934
Species: Homo sapiens
Compartment: nucleoplasm
Based on studies in mice, MECP2 directly stimulates transcription of the GAD1 (GAD67) gene, encoding glutamate decarboxylase, an enzyme involved in GABA synthesis (Chao et al. 2010).
Identifier: R-HSA-888572
Species: Homo sapiens
Compartment: cytosol
GAD1 (GAD67) is evenly spread throughout the neuronal cytoplasm and is invoved in GABA synthesis that is used for synaptogenesis, protection against neural injury and as an energy source through the GABA shunt.

Complex (4 results from a total of 4)

Identifier: R-HSA-888583
Species: Homo sapiens
Compartment: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
Identifier: R-HSA-947478
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-888570
Species: Homo sapiens
Compartment: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
Identifier: R-HSA-9022984
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (3 results from a total of 3)

Identifier: R-HSA-9022927
Species: Homo sapiens
MECP2 regulates expression of several genes involved in GABA (gamma-aminobutyric acid) signaling. Transcription of GAD1 (GAD67) and GAD2 (GAD65) genes is directly positively regulated by MECP2. GAD1 and GAD2 are components of the glutamic acid decarboxylase complex involved in production of the neurotransmitter GABA. Mice lacking Mecp2 from GABA-releasing neurons have decreased GABA levels and exhibit multiple Rett syndrome features (Chao et al. 2010).

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).

Identifier: R-HSA-1236394
Species: Homo sapiens
Compartment: cytosol, extracellular region, plasma membrane
ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR/HER1), ERBB2 (HER2/NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed).

ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the related neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation. The promiscuous heteromerization of ERBBs adds combinatorial diversity to ERBB signaling processes. As ERBB4 binds more ligands than other ERBBs, but has restricted expression, ERBB4 expression channels responses to ERBB ligands. The signaling capabilities of the four receptors have been compared (Schulze et al. 2005).

As for other receptor tyrosine kinases, ERBB4 signaling effectors are largely dictated through binding of effector proteins to ERBB4 peptides that are phosphorylated upon ligand binding. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000).

The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000).

Besides signaling as a conventional transmembrane receptor kinase, ERBB4 differs from other ERBBs in that JM-A isoforms signal through efficient release of a soluble intracellular domain. Ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. For example, in mammary cells, ERBB4 binds SH2 transcription factor STAT5A. ERBB4 s80 shuttles STAT5A to the nucleus, and actsa as a STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Jones et al. 1999, Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 binds activated estrogen receptor in the nucleus and acts as a transcriptional co-factor in promoting transcription of some estrogen-regulated genes, including progesterone receptor gene NR3C3 and CXCL12 (SDF1) (Zhu et al. 2006). In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and is a co-regulator of YAP1-mediated transcription in association with TEAD transcription factors (Komuro et al. 2003, Omerovic et al. 2004). Hence, the WW binding motif couples ERBB4 to the major effector arm of the HIPPO signaling pathway. The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005).

WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).

ERBB4 also binds the E3 ubiquitin ligase MDM2, and inhibitor of p53 (Arasada et al. 2005). Other proteins that bind to ERBB4 intracellular domain have been identified by co-immunoprecipitation and mass spectrometry (Gilmore-Hebert et al., 2010), and include transcriptional co-repressor TRIM28/KAP1, which promotes chromatin compaction. DNA damage signaling through ATM releases TRIM28-associated heterochromatinization. Interactions of ERBB4 with TRIM28 and MDM2 may be important for integration of growth factor responses and DNA damage responses.

In human breast cancer cell lines, ERBB4 activation enhances anchorage-independent colony formation in soft agar but inhibits cell growth in a monolayer culture. Different ERBB4 ligands induce different gene expression changes in breast cancer cell lines. Some of the genes induced in response to ERBB4 signaling in breast cancer cell lines are RAB2, EPS15R and GATA4. It is not known if these gene are direct transcriptional targets of ERBB4 (Amin et al. 2004).

Transcriptome and ChIP-seq comparisons of full-length and intracellular domain isoforms in isogenic MCF10A mammary cell background have revealed the diversification of ERBB4 signaling engendered by alternative splicing and cleavage (Wali et al., 2014). ERBB4 broadly affected protease expression, cholesterol biosynthesis, HIF1-alpha signaling, and HIPPO signaling pathways, and other pathways were differentially activated by CYT1 and CYT2 isoforms. For example, CYT1 promoted expression of transcription factors TWIST1 and SNAIL1 that promote epithelial-mesenchymal transition. HIF1-alpha and HIPPO signaling are mediated, respectively, by binding of ERBB4 to HIF1-alpha and to YAP (Paatero et al., 2012, Komuro et al., 2003). ERBB4 increases activity of the transcription factor SREBF2, resulting in increased expression of SREBF2-target genes involved in cholesterol biosynthesis. The mechanism is not known and may involve facilitation of SREBF2 cleavage through ERBB4-mediated PI3K signaling (Haskins et al. 2016).

In some contexts, ERBB4 promotes growth suppression or apoptosis (Penington et al., 2002). Activation of ERBB4 in breast cancer cell lines leads to JNK dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka Cook et al. 2006). The nature of growth responses may be connected with the spliced isoforms expressed. In comparisons of CYT1 vs CYT2 (full-length and ICD) expression in mammary cells, CYT1 was a weaker growth inducer, associated with attenuated MAPK signaling relative to CYT2 (Wali et al., 2014). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro apoptotic factor (Naresh et al. 2006).

ERBB4 plays important roles in the developing and adult nervous system. Erbb4 deficiency in somatostatin-expressing neurons of the thalamic reticular nucleus alters behaviors dependent on sensory selection (Ahrens et al. 2015). NRG1-activated ERBB4 signaling enhances AMPA receptor responses through PKC-dependent AMPA receptor exocytosis. This results in an increased excitatory input to parvalbumin-expressing inhibitory neurons in the visual cortex and regulates visual cortical plasticity (Sun et al. 2016). NRG1-activated ERBB4 signaling is involved in GABAergic activity in amygdala which mediates fear conditioning (fear memory) (Lu et al. 2014). Conditional Erbb4 deletion from fast-spiking interneurons, chandelier and basket cells of the cerebral cortex leads to synaptic defects associated with increased locomotor activity and abnormal emotional, social and cognitive function that can be linked to some of the schizophrenia features. The level of GAD1 (GAD67) protein is reduced in the cortex of conditional Erbb4 mutants. GAD1 is a GABA synthesizing enzyme. Cortical mRNA levels of GAD67 are consistently decreased in schizophrenia (Del Pino et al. 2014). Erbb4 is expressed in the GABAergic neurons of the bed nucleus stria terminalis, a part of the extended amygdala. Inhibition of NRG1-triggered ERBB4 signaling induces anxiety-like behavior, which depends on GABAergic neurotransmission. NRG1-ERBB4 signaling stimulates presynaptic GABA release, but the exact mechanism is not known (Geng et al. 2016). NRG1 protects cortical interneurons against ischemic brain injury through ERBB4-mediated increase in GABAergic transmission (Guan et al. 2015). NRG2-activated ERBB4 can reduce the duration of GABAergic transmission by binding to GABA receptors at the postsynaptic membrane via their GABRA1 subunit and promoting endocytosis of GABA receptors (Mitchell et al. 2013). NRG1 promotes synchronization of prefrontal cortex interneurons in an ERBB4 dependent manner (Hou et al. 2014). NRG1-ERBB4 signaling protects neurons from the cell death induced by a mutant form of the amyloid precursor protein (APP) (Woo et al. 2012).

Clinical relevance of ERBB4 has been identified in several contexts. In cancer, putative and validated gain-of-function mutations or gene amplification that may be drivers have been identified at modest frequencies, and may also contribute to resistance to EGFR and ERBB2-targeted therapies. This is noteworthy as ERBB4 kinase activity is inhibited by pan-ERBB tyrosine kinase inhibitors, including lapatinib, which is approved by the US FDA. The reduced prevalence relative to EGFR and ERBB2 in cancer may reflect more restricted expression of ERBB4, or differential signaling, as specific ERBB4 isoforms have been linked to growth inhibition or apoptosis in experimental systems. ERBB2/ERBB4 heterodimers protect cardiomyocytes, so reduced activity of ERBB4 in patients treated with the ERBB2-targeted therapeutic antibody trastuzumab may contribute to the cardiotoxicity of this agent when used in combination with (cardiotoxic) anthracyclines.

With the importance of ERBB4 in developing and adult nervous system, NRG1 and/or ERBB4 polymorphisms, splicing aberrations and mutations have been linked to nervous system disorders including schizophrenia and amyotrophic lateral sclerosis, although these findings are not yet definitive.
Identifier: R-HSA-8986944
Species: Homo sapiens
MECP2 is an X chromosome gene whose loss-of-function mutations are an underlying cause of the majority of Rett syndrome cases. The MECP2 gene locus consists of four exons. Both exon 1 and exon 2 contain translation start sites. Alternative splicing of the second exon results in expression of two MECP2 transcript isoforms, MECP2_e1 (MECP2B or MECP2alpha) and MECP2_e2 (MECP2A or MECP2beta). The N-terminus of the MECP2_e1 isoform, in which exon 2 is spliced out, is encoded by exon 1. The N-terminus of the MECP2_e2 isoforms, which includes both exon 1 and exon 2, is encoded by exon 2, as the exon 2 translation start site is used. Exons 3 and 4 are present in both isoforms. The MECP2_e2 isoform was cloned first and is therefore more extensively studied. The MECP2_e1 isoform is more abundant in the brain (Mnatzakanian et al. 2004, Kriaucionis and Bird 2004, Kaddoum et al. 2013). Mecp2 isoforms show different expression patterns during mouse brain development and in adult brain regions (Dragich et al. 2007, Olson et al. 2014). While Rett syndrome mutations mainly occur in exons 3 and 4 of MECP2, thereby affecting both MECP2 isoforms (Mnatzakanian et al. 2004), some mutations occur in exon 1, affecting MECP2_e1 only. No mutations have been described in exon 2 (Gianakopoulos et al. 2012). Knockout of Mecp2_e1 isoform in mice, through a naturally occurring Rett syndrome point mutation which affects the first translation codon of MECP2_e1, recapitulates Rett-like phenotype. Knockout of Mecp2_e2 isoform in mice does not result in impairment of neurologic functions (Yasui et al. 2014). In Mecp2 null mice, transgenic expression of either Mecp2_e1 or Mecp2_e2 prevents development of Rett-like phenotype, with Mecp2_e1 rescuing more Rett-like symptoms than Mecp2_e2. This indicates that both splice variants can fulfill basic Mecp2 functions in the mouse brain (Kerr et al. 2012). Changes in gene expression upon over-expression of either MECP2_e1 or MECP2_e2 imply overlapping as well as distinct target genes (Orlic-Milacic 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).

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