title: Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders.
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 MeCP2(lo) and MeCP2(hi). 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 MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) 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.
authors.affiliation: Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis 95616, USA.
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Samaco
authors.forename: Raman P
authors.initials: RP
authors.lastname: Nagarajan
authors.forename: Daniel
authors.initials: D
authors.lastname: Braunschweig
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D000293:Adolescent; D000328:Adult; D017204:Angelman Syndrome / Q000378:metabolism; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000378:metabolism; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D003592:Cytophotometry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005625:Frontal Lobe / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051783:Methyl-CpG-Binding Protein 2; D020411:Oligonucleotide Array Sequence Analysis; D026723:Polyadenylation / Q000235:genetics; D011218:Prader-Willi Syndrome / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins