title: Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations.
abstract: Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.
authors.affiliation: Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Simonet
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: C Nicole
authors.initials: CN
authors.lastname: Sunnen
authors.affiliation: Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jue
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.affiliation: Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Current address: Division of Child Neurology, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19072, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Marsh
mesh_terms: D000818:Animals; D058256:Brain Waves / Q000235:genetics*; D002755:Choice Behavior / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D003623:Dark Adaptation / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012903:Smell / Q000235:genetics; D013687:Telencephalon / Q000254:growth & development* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors
keywords: anxiety; hyperactivity; learning; mouse; socialization