Hori Kei, Nagai Taku, Shan Wei, Sakamoto Asami, Taya Shinichiro, Hashimoto Ryoya, Hayashi Takashi, Abe Manabu, Yamazaki Maya, Nakao Keiko, Nishioka Tomoki, Sakimura Kenji, Yamada Kiyofumi, Kaibuchi Kozo, Hoshino Mikio
Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Cell Rep. 2014 Dec 24;9(6):2166-79. doi: 10.1016/j.celrep.2014.11.045. Epub 2014 Dec 18.
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.
自闭症易感候选基因2（AUTS2）发生突变时，其蛋白质被认为在神经元细胞核中发挥作用，这与多种精神疾病有关，包括自闭症谱系障碍、智力残疾和精神分裂症。在此我们表明，细胞质中的AUTS2参与细胞骨架的调节和神经发育。免疫组织化学和分级分离研究表明，AUTS2不仅定位于细胞核，也定位于细胞质，包括发育中大脑的生长锥。AUTS2激活Rac1以诱导片状伪足，但下调Cdc42以抑制丝状伪足。我们的功能丧失和拯救实验表明，细胞质中的AUTS2-Rac1途径参与发育中大脑的皮质神经元迁移和神经突形成。这些发现表明，细胞质中的AUTS2作为Rho家族GTP酶的调节剂，有助于大脑发育，并为深入了解患有AUTS2突变的人类精神疾病的病理学提供了线索。
