Publication Date:
2013-06-19
Description:
Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that, in neurons, regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome. By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3',5'-cyclic AMP (cAMP), indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MeCP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922283/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922283/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ebert, Daniel H -- Gabel, Harrison W -- Robinson, Nathaniel D -- Kastan, Nathaniel R -- Hu, Linda S -- Cohen, Sonia -- Navarro, Adrija J -- Lyst, Matthew J -- Ekiert, Robert -- Bird, Adrian P -- Greenberg, Michael E -- 092076/Wellcome Trust/United Kingdom -- K08 MH090306/MH/NIMH NIH HHS/ -- K08MH90306/MH/NIMH NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P30-HD 18655/HD/NICHD NIH HHS/ -- R01 NS048276/NS/NINDS NIH HHS/ -- R01NS048276/NS/NINDS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 18;499(7458):341-5. doi: 10.1038/nature12348.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23770587" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cells, Cultured
;
Co-Repressor Proteins/*metabolism
;
Humans
;
Methyl-CpG-Binding Protein 2/chemistry/genetics/*metabolism
;
Mice
;
Mutation
;
Neurons/metabolism
;
Phosphorylation
;
Rett Syndrome/genetics
;
Threonine/*metabolism
;
Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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