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Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function.

Neuron | 2011

Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.

Pubmed ID: 21982370 RIS Download

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Associated grants

  • Agency: NIMH NIH HHS, United States
    Id: K08MH90306
  • Agency: NINDS NIH HHS, United States
    Id: R00 NS058391
  • Agency: NIDA NIH HHS, United States
    Id: R01 DA022202
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-04
  • Agency: NCI NIH HHS, United States
    Id: T32CA009361
  • Agency: NINDS NIH HHS, United States
    Id: 1R01NS048276
  • Agency: NINDS NIH HHS, United States
    Id: 1R21NS070250-01A1
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-07
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-06S1
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-02
  • Agency: NINDS NIH HHS, United States
    Id: K99 NS058391
  • Agency: NIH HHS, United States
    Id: DP2 OD006461
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS070250
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-05
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-06
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-01
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007753
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-03
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276-08
  • Agency: NIMH NIH HHS, United States
    Id: K08 MH090306
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS048276
  • Agency: NCI NIH HHS, United States
    Id: T32 CA009361

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Neurolucida (tool)

RRID:SCR_001775

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