Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders

Rodney C. Samaco, Raman P. Nagarajan, Daniel Braunschweig, Janine M LaSalle

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2lo and MeCP2hi. To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2hi cells with age that could be explained by increased MECP2 transcription within the MeCP2hi population. A significant decrease in the relative usage of the long transcript in the MeCP2lo population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.

Original languageEnglish (US)
Pages (from-to)629-639
Number of pages11
JournalHuman Molecular Genetics
Volume13
Issue number6
DOIs
StatePublished - Mar 15 2004

ASJC Scopus subject areas

  • Genetics

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