AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders

Abstract

AbstractAutism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features. TheAUTS2syndrome phenotype includes borderline to severe intellectual disability (ID), microcephaly and mild dysmorphic traits. Specific ASD-like features, including obsessive or ritualistic behaviours, are frequently displayed, although sociability is largely unaffected. Syndrome severity is worse when mutations are present in the 3’ region (exons 9-19) of theAUTS2gene.AUTS2is also associated with alcohol consumption, heroin dependence, schizophrenia and dyslexia, using GWAS studies. Our working hypothesis is thatAUTS2expression during mammalian evolution can be instrumental to predict phenotypes linked to the disease. For that, we studied brain In Situ Hybridization (ISH) data in mouse, marmoset, human embryo and fetuses and sequences data of Neanderthal, Denisovan and modern humans. Developmental mouse brain expression is found in neocortex, hippocampus, thalamus, tegmentum and cerebellum suggesting a link linked with cognition, stereotypies and perseverative behaviors. Expression in amygdala and claustrum found in marmoset extend these phenotypes to anxiety and higher-order cognitive processes. In human embryos (8 weeks) and fetuses (15- and 19-weeks), we foundAUTS2expression in similar regions but also in medial, lateral and caudal ganglionic eminence, that are involved in the diversity of interneurons found in neocortex, hippocampus and striatum. Sequence comparison ofAUTS2locus in Neanderthal, Denisova and modern human reveals novel sites in regulatory regions ofAUTS2. Altogether, these results suggest that ISH distribution along mammals is a novel phenotype-related biomarker useful for translational research.