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.

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

“…Indeed, it has been described as a locus that confers risk across neurodevelopmental diagnostic boundaries4680. The functions of the AUTS2 protein are largely unknown but it has been suggested to play a role in cytoskeletal regulation81. The STARD9 gene encodes a mitotic kinesin which functions in spindle pole assembly82.…”

A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

“…The faint extension creases and mild contractures of the fingers are both likely to be caused by the aberrant fetal development, primarily caused by the AUTS2 defect or secondary through lack of movement in utero caused by the AUTS2 defect 24. As AUTS2 is highly expressed in the developing brain and the functional clues at the molecular and protein level so far also indicate an important role in neuron development, one could hypothesise that diminished movements in utero (for neurological reasons) are causing these defects 1 3 4 5. However, embryological studies did show more evidence for the theory that the same genetic factors are responsible for flexion crease formation as well as development for joint movement.…”

“…AUTS2 activates gene expression in the central nervous system by binding to the polycomb repressive complex 1.5 (that normally suppresses gene transcription by chromatin remodelling) 4. The full-length AUTS2 transcript is located in the cytoplasm and in the nucleus, whereas the shorter transcript starting in exon 9 is only located in the nucleus 2 5. The cytoplasmic AUTS2 is important in cytoskeletal regulation.…”

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization

“…Accumulating evidence has confirmed that the extra ROS produced during neural oxidative stress could alter the arrangement of neuronal cytoskeleton 4, 5. Since the cytoskeleton plays crucial roles in a variety of neuronal physiological processes, including organelle and vesicular trafficking, maintenance of basic architecture and polarity, neuritogenesis and migration 6-9. It is acknowledged that the cytoskeletal dysfunction has been implicated as an underlying cause of neuronal apoptosis, and even cell death in CNS diseases 10.…”