The autism susceptibility candidate 2 (AUTS2) gene has been found to be responsible for various brain developmental disorders. Diverse structural alterations of the gene have been implicated in conditions like autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), depression, epilepsy, intellectual disability (ID), and language disorder. Particularly, people with AUTS2 syndrome strongly exhibit ADHD, ID, and ASD. 
In addition, patients with AUTS2 mutations also manifest growth defects such as low birth weight, musculoskeletal anomalies, craniofacial dysmorphisms, short stature, developmental delay, and microcephaly, in a syndromic pattern.
AUTS2 has been implicated in microcephaly; reports record a 65% occurrence rate in people with AUTS2 gene mutation. In mice models, there have been manifestations of features that imitate the ones seen in humans. Magnetic resonance imaging (MRI) of human brains has yielded reduced cerebral content and cerebellar and corpus callosum hyperplasia. In mice, cerebellar hypoplasia has been seen but cerebral hypoplasia.
AUTS2 causes suppression
In the mammalian cerebral cortex, the radial glial cells (RGC) and intermediate progenitor cells (IPC) are progenitor cells that are responsible for deeper and upper-layer neuron development. Microcephaly is caused by the reduction in the number of cortical neurons. While the development and differentiation of RGCs is well known, the IPC pathway has not been fully researched and understood.
A previous study has provided evidence of AUTS2 missense mutation via reduced cortical volume and ventricular enlargement on MRI scans. The AUTS2 gene is strongly involved in the transcription process that happens in the nucleus of IPCs, also evidenced by some studies. AUTS2 interacts with polycomb repressive complex 1 (PCR1) to function as a transcriptional regulator.
Shimaoka et al. discovered that the interaction of the AUTS2 gene with PCR2 in the nucleus of IPCs influences chromatin modifications and causes repression of genetic transcription in mice. They found various genes, however, AUTS2 bound more to specific genomic regions.
They also demonstrated PCR2 binding alongside AUTS2 to these genomes. In addition, they propose that the AUTS2/PCR2 carry out gene suppression by the trimethylation of the H3K27 protein.
Furthermore, the expression of the activation and repression function of AUTS2 depends on the type of cell, as seen in H3K27. It shows increased activity in HEK293 and decreased activity in Neuro2a cells.
Implications
These findings confirm that AUTS2 regulates the development and differentiation of cerebral cortical neurons. They contribute to our understanding of the pathogenesis of AUTS2 syndrome, the regulatory mechanisms that control gene expression, and therapeutic strategies to treat the syndrome and disorders associated with it.
On a larger scale, the study also leads to a better understanding of the evolution of the mammalian brain. Throughout their evolutionary history, mammals have acquired new IPCs, which have helped to expand the mammalian cerebral cortex.
References
Shimaoka K, Hori K, Miyashita S, et al. AUTS2, a causative gene for microcephaly, regulates division of intermediate progenitor cells and production of upper-layer neurons. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2024.04.15.589462
