title: Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development.
abstract: Methyl CpG-binding protein 2 gene (MeCP2) mutations are implicated in Rett syndrome (RTT), one of the common causes of female mental retardation. Two MeCP2 isoforms have been reported: MeCP2_e2 (splicing of all four exons) and MeCP2_e1 (alternative splicing of exons 1, 3, and 4). Their relative expression levels vary among tissues, with MeCP2_e1 being more dominant in adult brain, whereas MeCP2_e2 is expressed more abundantly in placenta, liver, and skeletal muscle. In this study, we performed specific disruption of the MeCP2_e2-defining exon 2 using the Cre-loxP system and examined the consequences of selective loss of MeCP2_e2 function in vivo. We performed behavior evaluation, gene expression analysis, using RT-PCR and real-time quantitative PCR, and histological analysis. We demonstrate that selective deletion of MeCP2_e2 does not result in RTT-associated neurological phenotypes but confers a survival disadvantage to embryos carrying a MeCP2_e2 null allele of maternal origin. In addition, we reveal a specific requirement for MeCP2_e2 function in extraembryonic tissue, where selective loss of MeCP2_e2 results in placenta defects and up-regulation of peg-1, as determined by the parental origin of the mutant allele. Taken together, our findings suggest a novel role for MeCP2 in normal placenta development and illustrate how paternal X chromosome inactivation in extraembryonic tissues confers a survival disadvantage for carriers of a mutant maternal MeCP2_e2 allele. Moreover, our findings provide an explanation for the absence of reports on MeCP2_e2-specific exon 2 mutations in RTT. MeCP2_e2 mutations in humans may result in a phenotype that evades a diagnosis of RTT.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira 187-8502, Japan. itoh@ncnp.go.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Candice G T
authors.initials: CG
authors.lastname: Tahimic
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ide
authors.forename: Akihiro
authors.initials: A
authors.lastname: Otsuki
authors.forename: Toshikuni
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kurimasa
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D010920:Placenta / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D011485:Protein Binding; D020033:Protein Isoforms; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms