Cell Reports
Volume 9, Issue 6, 24 December 2014, Pages 2166-2179
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Article
Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

https://doi.org/10.1016/j.celrep.2014.11.045Get rights and content
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Highlights

  • AUTS2 localizes in both the nuclei and cytoplasm of neurons

  • Cytoplasmic AUTS2 regulates Rho family GTPases to control actin dynamics

  • AUTS2 is involved in neurite outgrowth and branch formation in neurons

  • AUTS2 controls neuronal migration via Rac1 signaling pathway

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).