title: Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.
abstract: Gene abnormalities in RBFOX1, encoding an mRNA-splicing factor, have been shown to cause autism spectrum disorder and other neurodevelopmental disorders. Since pathophysiological significance of the dominant nuclear isoform in neurons, RBFOX1-isoform1 (iso1), remains to be elucidated, we performed comprehensive analyses of Rbfox1-iso1 during mouse corticogenesis. Knockdown of Rbfox1-iso1 by in utero electroporation caused abnormal neuronal positioning during corticogenesis, which was attributed to impaired migration. The defects were found to occur during radial migration and terminal translocation, perhaps due to impaired nucleokinesis. Axon extension and dendritic arborization were also suppressed in vivo in Rbfox1-iso1-deficient cortical neurons. In addition, electrophysiology experiments revealed significant defects in the membrane and synaptic properties of the deficient neurons. Aberrant morphology was further confirmed by in vitro analyses; Rbfox1-iso1-konckdown in hippocampal neurons resulted in the reduction of primary axon length, total length of dendrites, spine density and mature spine number. Taken together, this study shows that Rbfox1-iso1 plays an important role in neuronal migration and synapse network formation during corticogenesis. Defects in these critical processes may induce structural and functional defects in cortical neurons, and consequently contribute to the pathophysiology of neurodevelopmental disorders with RBFOX1 abnormalities.
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.|Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Hamada
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Nishijo
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Morishita
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 Pharmacology, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Momiyama
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: K
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000502:physiology; D001921:Brain / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D055495:Neurogenesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D000072260:RNA Splicing Factors; C465036:Rbfox1 protein, mouse