Auts2 enhances neurogenesis and promotes expansion of the cerebral cortex

Introduction: The AUTS2 gene is associated with various neurodevelopmental and psychiatric disorders and has been suggested to play a role in acquiring human-specific traits. Functional analyses of Auts2 knockout mice have focused on postmitotic neurons, and the reported phenotypes do not faithfully recapitulate the whole spectrum of AUTS2-related human diseases. Objective: The objective of the study is to assess the role of AUTS2 in the biology of neural progenitor cells, cortical neurogenesis and expansion; and understand how its deregulation leads to neurological disorders. Methods: We screened the literature and conducted a time point analysis of AUTS2 expression during cortical development. We used in utero electroporation to acutely modulate the expression level of AUTS2 in the developing cerebral cortex in vivo, and thoroughly characterized cortical neurogenesis and morphogenesis using immunofluorescence, cell tracing and sorting, transcriptomic profiling, and gene ontology enrichment analyses. Results: In addition to its expression in postmitotic neurons, we showed that AUTS2 is also expressed in neural progenitor cells at the peak of neurogenesis. Upregulation of AUTS2 dramatically altered the differentiation program and fate determination of cortical progenitors. Notably, it increased the number of basal progenitors and neurons and changed the expression of hundreds of genes, among which 444 have not been implicated in mouse brain development or function. Conclusion: The study provides evidence that AUTS2 is expressed in germinal zones and plays a key role in fate decision of neural progenitor cells with impact on corticogenesis. It also presents comprehensive lists of AUTS2 target genes thus advancing the molecular mechanisms underlying AUTS2-associated diseases and the evolutionary expansion of the cerebral cortex.