title: Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains.
abstract: Rett syndrome (RTT) is a major neurodevelopmental disorder, characterized by mental retardation and autistic behavior. Mutation of the MeCP2 gene, encoding methyl CpG-binding protein 2, causes the disease. The pathomechanism by which MeCP2 dysfunction leads to the RTT phenotype has not been elucidated. We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. A chromatin immunoprecipitation assay showed that the IGFBP3 promoter contained an MeCP2 binding site. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. Moreover, mecp2-null mice showed a widely distributed and increased number of IGFBP3-positive cells in the cerebral cortex, whereas wild-type mice at the same age showed fewer IGFBP3-positive cells. These results suggest that IGFBP3 is a downstream gene regulated by MeCP2 and that the previously reported BDNF and DLX5 genes and MeCP2 may contribute directly to the transcriptional expression of IGFBP3 in the brain. Interestingly, the pathologic features of mecp2-null mice have some similarities to those of IGFBP3-transgenic mice, which show a reduction of early postnatal growth. IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. itoh@ncnp.go.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ide
authors.forename: Sachio
authors.initials: S
authors.lastname: Takashima
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kudo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nomura
authors.forename: Masaya
authors.initials: M
authors.lastname: Segawa
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.forename: Hideo
authors.initials: H
authors.lastname: Mori
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horie
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000254:growth & development* / Q000378:metabolism* / Q000503:physiopathology; D002452:Cell Count; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2