title: Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis.
abstract: Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations.
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Hori
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Taya
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Ryoya
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Nigata 951-8585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Nigata 951-8585, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Nigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan. Electronic address: hoshino@ncnp.go.jp.
authors.forename: Mikio
authors.initials: M
authors.lastname: Hoshino
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D014157:Transcription Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C549397:Auts2 protein, mouse; D003598:Cytoskeletal Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; C484602:Rac1 protein, mouse; D014157:Transcription Factors; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein