Neuronal Migration and AUTS2 Syndrome

Abstract

Neuronal migration is one of the pivotal steps to form a functional brain, and disorganization of this process is believed to underlie the pathology of psychiatric disorders including schizophrenia, autism spectrum disorders (ASD) and epilepsy. However, it is not clear how abnormal neuronal migration causes mental dysfunction. Recently, a key gene for various psychiatric diseases, the Autism susceptibility candidate 2 (AUTS2), has been shown to regulate neuronal migration, which gives new insight into understanding this question. Interestingly, the AUTS2 protein has dual functions: Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1). In this review, we discuss AUTS2 from the viewpoint of human genetics, molecular function, brain development, and behavior in animal models, focusing on its role in neuronal migration.

Keywords: AUTS2 syndrome; Autism; PRC1; Rac1; cytoskeleton; intellectual disabilities; neuritogenesis; neuronal migration.

Figure 1

Schematic of AUTS2 genomic region and the protein structure of AUTS2 isoforms. Genomic structure of human AUTS2 locus in chromosome 7 (Chr.7) (A) and protein structure of the representative five different mouse AUTS2 isoforms (B) are depicted. The exons (blue squares in A) corresponding to the protein regions are indicated with solid lines. Ex: exon, PR: proline-rich domain.

Figure 2

AUTS2-Rac signaling pathways in neuronal migration and neuritogenesis. (A) At the developing cerebral cortex, AUTS2 acts as an upstream factor for the P-Rex1-Rac1 signaling pathway to control the neuronal migration regulating the cytoskeletal rearrangements; (B) After completion of migration, AUTS2 activates Rac1 via the Elmo2/Dock180 complex and promotes the neurite extensions of cortical neurons. CP: cortical plate, IZ: intermediate zone, JNK: c-Jun N-terminal kinase, MTs: microtubules, VZ/SVZ: ventricular/subventricular zone.