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Cell Rep. 2014 Dec 24;9(6):2166-79. doi: 10.1016/j.celrep.2014.11.045. Epub 2014 Dec 18.

Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis.

Author information

1
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
2
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
3
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.
4
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Nigata 951-8585, Japan.
5
Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
6
Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan.
7
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan. Electronic address: hoshino@ncnp.go.jp.

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.

PMID:
25533347
DOI:
10.1016/j.celrep.2014.11.045
[Indexed for MEDLINE]
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