title: Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders.
abstract: In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c.1499 G > A (p.R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type Nr1d1, but not by the c.1499 G > A mutant. Time-lapse imaging revealed characteristic abnormal migration phenotypes in Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. These results suggest that functional defects in NR1D1 may be related to ASD etiology and pathophysiology.
authors.affiliation: Department of Pediatrics, Jichi medical university, Tochigi, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Department of Pediatrics, Jichi medical university, Tochigi, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, Jichi medical university, Tochigi, Japan.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Jichi medical university, Tochigi, Japan.
authors.forename: Eriko F
authors.initials: EF
authors.lastname: Jimbo
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Tabata
authors.affiliation: Department of Pediatrics, Jichi medical university, Tochigi, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamagata
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.|Department of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Koh-Ichi
authors.initials: KI
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000503:physiopathology*; D002465:Cell Movement; D002540:Cerebral Cortex / Q000196:embryology* / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D059008:Time-Lapse Imaging
chemical_list: D050505:Mutant Proteins; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1