MeCP2 Deficiency in the Brain Decreases BDNF Levels by REST/CoREST-Mediated Repression and Increases TRKB Production

Abuhatzira, Liron; Makedonski, Kirill; Kaufman, Yotam; Razin, Aharon; Shemer, Ruth

doi:10.4161/epi.2.4.5212

Cited by 121 publications

(94 citation statements)

References 36 publications

(57 reference statements)

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“…Although the exact mechanism for this is yet to be determined, it is possible to speculate that de-repression of miR-124 during withdrawal to cocaine might be involved in NAC1 induction. Our observation of REST induction after chronic cocaine is contradictory to earlier findings that REST suppresses BDNF expression in Huntington's disease (Zuccato et al, 2003) and in the brain of Rett syndrome patients (Abuhatzira et al, 2007). However a truncated, neuronal-specific REST isoform, REST4, has been described which can complete the silencing effect of REST/NRSF (Tabuchi et al, 2002).…”

Section: Article In Presscontrasting

confidence: 99%

microRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

Chandrasekar

Dreyer

2009

Molecular and Cellular Neuroscience

258

229

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Available online xxxxMicroRNAs play key regulatory roles in cellular processes including neurogenesis, synapse development and plasticity in the brain. Psychostimulants induces strong neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. MicroRNA profiling for identifying miRNAs regulating cocaineinduced, plasticity-related genes revealed significant regulation of a set of miRNAs upon cocaine administration, especially let-7d, miR-181a and the brain-specific miR-124. These miRNAs target many genes involved in cocaine addiction. Precursor and mature miRNA quantification by qRT-PCR showed that miR-124 and let-7d are significantly downregulated, whereas miR-181a is induced in the mesolimbic dopaminergic system under chronic cocaine administration. Results were confirmed by in situ hybridization, Northern blots, FISH analysis and RNase protection assay. Using lentiviral-mediated miRNA expression, we show a significant downregulation of BDNF and D3R both at mRNA and protein levels by miR-124 and let-7d, respectively. Our data suggest that miR-124, let-7d and miR-181a may be involved in a complex feedback loop with cocaine-responsive plasticity genes, highlighting the possibility that some miRNAs are key regulators of the reward circuit and may be implicated in addiction.

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Section: Article In Presscontrasting

confidence: 99%

microRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

Chandrasekar

Dreyer

2009

Molecular and Cellular Neuroscience

258

229

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“…How does MeCP2 regulate KCC2? Previous studies have reported that MeCP2 can regulate the transcriptional repressor REST, a master regulator of neuronal gene expression (35,36). Interestingly, KCC2 has been reported to be regulated by REST (37).…”

Section: Resultsmentioning

confidence: 99%

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Tang

Kim

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

195

179

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Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K+-Cl− cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

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“…3A). Given that MeCP2 affects BDNF transcription through mechanisms including CREB signaling (16,42), we measured BDNF expression. Indeed, levels of both cerebellar BDNF mRNA and protein were reduced in KOv mice relative to WT controls but significantly increased in KOt mice, suggesting that clenbuterol can ameliorate the alterations in BDNF expression observed in Mecp2 KO mice (Fig.…”

Section: Igf1 Is Reduced In Mecp2 Mutant Mice Through a Mirna-mediatedmentioning

confidence: 99%

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Mellios

Woodson

Garcia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2 −/y ) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2 −/+ ) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2 −/y mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.let-7f | LIN28A

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MeCP2 Deficiency in the Brain Decreases BDNF Levels by REST/CoREST-Mediated Repression and Increases TRKB Production

Cited by 121 publications

References 36 publications

microRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

microRNAs miR-124, let-7d and miR-181a regulate Cocaine-induced Plasticity

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

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