MeCP2 expression and function during brain development: Implications for Rett syndrome's pathogenesis and clinical evolution

Walter E. Kaufmann, Michael V. Johnston, Mary E. Blue

Research output: Contribution to journalArticlepeer-review

Abstract

Most cases of Rett syndrome (RTT) are associated with mutations of the transcriptional regulator MeCP2. On the basis of molecular structure, ontogeny, and subcellular and regional distribution, MeCP2 appears to be a link between synaptic activity and neuronal transcription. Integrating data on MeCP2 neurobiology, RTT neurobiology, MeCP2 mutational patterns in RTT and other disorders, histone profiles of relevance to RTT, and genotype-phenotype correlations in RTT, we update here our synaptic hypothesis of RTT. We postulate that MeCP2 dysfunction leads to abnormal brain development through maladjustment of neuronal gene expression to synaptic and other extra-cellular signals, mainly during the critical period of synaptic maturation. RTT phenotype will develop, only if severe MeCP2 dysfunction is present during early neuronal differentiation. Two models are proposed for explaining general and regional neuronal abnormalities in RTT and the phenotypical outcome of MeCP2 dysfunction, respectively.

Original languageEnglish (US)
Pages (from-to)S77-S87
JournalBrain and Development
Volume27
Issue numberSUPPL. 1
DOIs
StatePublished - Nov 2005

Keywords

  • MeCP2
  • Phenotype
  • Plasticity
  • Rett syndrome
  • Synapse

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Clinical Neurology

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