Autism-related gene intergenerationally regulates neurodevelopment and behavior in fish through non-genetic mechanisms

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Abstract Parental stress can impact progeny neurodevelopment and long-term behavior through gamete-mediated non-genetic inheritance (i.e., by mechanisms that do not involve transmission of genetic alleles). While intergenerational effects have been studied in males, maternal non-genetic mechanisms shaping long-term progeny behavior remain unknown in vertebrates. We focused on AUTS2, a gene maternally repressed in the fish oocyte following maternal stress and associated with human neurodevelopmental disorders (NDDs). Here we show, using a model fish species, that maternal auts2a (the ortholog of human AUTS2) loss of function impacts progeny long-term behavior and modulates gene expression in neural cells during early neurodevelopment, including NDD-associated genes. We found that auts2a expression in the mother/oocyte regulates maternally-inherited factors, particularly transcriptional and post-transcriptional regulators required for early embryonic development before zygotic genome activation. Our results unravel a non-genetic mechanism of maternal inheritance and shed new light on the intergenerational determinism of neurodevelopment and behavior in a vertebrate species. Moreover, we found that AUTS2 belongs to a group of 45 evolutionarily-conserved oocyte genes, associated with behavior and neurodevelopment in vertebrates and linked to severe human diseases, raising the question of the role of maternal factors in the determinism of NDDs.