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Hum Mol Genet. 2016 May 1;25(9):1690-702. doi: 10.1093/hmg/ddw038. Epub 2016 Feb 16.

Acute and crucial requirement for MeCP2 function upon transition from early to late adult stages of brain maturation.

Author information

  • 1Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA and.
  • 2Vollum Institute, Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA.
  • 3Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA and nurit.ballas@stonybrook.edu.

Abstract

Germline mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2), underlie most cases of Rett syndrome (RTT), an autism spectrum disorder affecting approximately one in 10 000 female live births. The disease is characterized in affected girls by a latent appearance of symptoms between 12 and 18 months of age while boys usually die before the age of two. The nature of the latency is not known, but RTT-like phenotypes are recapitulated in mouse models, even when MeCP2 is removed at different postnatal stages, including juvenile and adolescent stages. Unexpectedly, here, we show that within a very brief developmental window, between 10 (adolescent) and 15 (adult) weeks after birth, symptom initiation and progression upon removal of MeCP2 in male mice transitions from 3 to 4 months to only several days, followed by lethality. We further show that this accelerated development of RTT phenotype and lethality occur at the transition to adult stage (15 weeks of age) and persists thereafter. Importantly, within this abbreviated time frame of days, the brain acquires dramatic anatomical, cellular and molecular abnormalities, typical of classical RTT. This study reveals a new postnatal developmental stage, which coincides with full-brain maturation, where the structure/function of the brain is extremely sensitive to levels of MeCP2 and loss of MeCP2 leads to precipitous collapse of the neuronal networks and incompatibility with life within days.

PMID:
26908602
PMCID:
PMC4986326
[Available on 2017-05-01]
DOI:
10.1093/hmg/ddw038
[PubMed - in process]
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