title: Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice.
abstract: Several X-linked mental retardation syndromes are caused by mutations in the ATRX gene. Common clinical features associated with ATRX mutations include severe mental retardation, characteristic facial anomalies and variable degrees of urogenital defects and alpha-thalassemia. Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. Here we demonstrate that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Furthermore, we have generated transgenic mice that overexpress ATRX as an initial model for studying the function of this protein during development. Misexpression of ATRX was associated with growth retardation, neural tube defects and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death, as well as seizures, mild craniofacial anomalies and abnormal behavior. Our findings indicate that ATRX dosage is crucial for normal development and organization of the cortex, and emphasize the relevance of our model for the study of ATRX function and disease pathogenesis.
authors.affiliation: Ottawa Health Research Institute, Ottawa, Ontario, Canada.
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jagla
authors.forename: Cecelia
authors.initials: C
authors.lastname: Smeenk
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D004848:Epithelium / Q000196:embryology; D005260:Female; D005313:Fetal Death; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010641:Phenotype; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D000075924:X-linked Nuclear Protein
chemical_list: D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; D004265:DNA Helicases; C092332:ATRX protein, human; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein