title: A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos.
abstract: MeCP2 is a DNA binding protein that represses transcription of methylated genes in vitro, but the endogenous function of MeCP2 in vivo is unclear. Here, we demonstrate that in Xenopus laevis embryos MeCP2 is a partner of the SMRT corepressor complex that regulates the expression of a neuronal repressor xHairy2a in differentiating neuroectoderm. The MeCP2/SMRT complex is bound to the promoter of the silenced xHairy2a gene and is displaced upon activation by the Notch intracellular domain (NICD). A truncated form of MeCP2 (R168X) found in patients with Rett syndrome cannot interact with the SMRT complex or fully activate xHairy2a during primary neurogenesis. This disruption of MeCP2 activity results in abnormal patterning of primary neurons during neuronal differentiation. Our results support a model whereby the dynamic association of MeCP2 with methylated DNA and the SMRT complex regulates a gene involved in cell fate decisions during primary neurogenesis in Xenopus.
authors.affiliation: Genes and Development Group, School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Irina
authors.initials: I
authors.lastname: Stancheva
authors.forename: Anne L
authors.initials: AL
authors.lastname: Collins
authors.forename: Ingatia B
authors.initials: IB
authors.lastname: Van den Veyver
authors.forename: Huda
authors.initials: H
authors.lastname: Zoghbi
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014404:Tubulin / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; C497395:MECP2 protein, Xenopus; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D051880:Receptors, Notch; D012097:Repressor Proteins; D014404:Tubulin; D029867:Xenopus Proteins; D004247:DNA; D005982:Glutathione Transferase