TY - JOUR
T1 - Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis
AU - Hori, Kei
AU - Nagai, Taku
AU - Shan, Wei
AU - Sakamoto, Asami
AU - Taya, Shinichiro
AU - Hashimoto, Ryoya
AU - Hayashi, Takashi
AU - Abe, Manabu
AU - Yamazaki, Maya
AU - Nakao, Keiko
AU - Nishioka, Tomoki
AU - Sakimura, Kenji
AU - Yamada, Kiyofumi
AU - Kaibuchi, Kozo
AU - Hoshino, Mikio
N1 - Funding Information:
We thank members of the Hoshino lab for useful discussions. This work is supported by Grants-in-Aid for Scientific Research on Innovative Areas “Mesoscopic Neurocircuitry” (grant 25115733) and “Synapse and Neurocircuit Pathology” (grant 25110742) of the Ministry of Education, Culture, Sports, Science, and Technology of Japan; grants from MEXT, Astellas foundation, Naito foundation, Takeda foundation, Uehara foundation, Intramural Research Grants (M.H., 24-12, 25-3) for Neurological and Psychiatric Disorders of NCNP, Health Science Research Grant for Research on Psychiatric and Neurological Diseases and Mental Health (M.H., H23-001) from the Japanese Ministry of Health, Labor and Welfare, and JSPS KAKENHI grant numbers 23700406 and 25830030 (K.H.).
Publisher Copyright:
© 2014 The Authors.
PY - 2014/12/24
Y1 - 2014/12/24
N2 - 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 inthe 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.
AB - 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 inthe 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.
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U2 - 10.1016/j.celrep.2014.11.045
DO - 10.1016/j.celrep.2014.11.045
M3 - Article
C2 - 25533347
AN - SCOPUS:84919875159
VL - 9
SP - 2166
EP - 2179
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 6
ER -