Anthony Wynshaw-Boris and his colleagues are investigating the hypothesis that a subset of individuals with autism spectrum disorders (ASD) (approximately 25-30 percent) display early brain overgrowth. His lab has recently produced two relevant models that recapitulate important aspects of early brain overgrowth in ASD. First, the team produced a mouse model deficient for DVL1 and DVL3 (Dvl1/3 +/– mutants). These mice display adult social behavior abnormalities associated with transient embryonic brain enlargement during the time of deep-layer cortical formation¹. Second, they generated human induced pluripotent stem cell (iPSC) models by reprogramming fibroblasts obtained from individuals with ASD who had early head overgrowth and unaffected control individuals with normal head circumference. Neuronal progenitor cells (NPCs) derived from ASD iPSC lines displayed enhanced proliferation compared to control NPCs².  In both the Dvl 1/3 mutant mouse model and the human iPSCs, the observed phenotypes were caused by down-regulation of beta-catenin activity and its direct target BRN2. This remarkable conservation of beta-catenin and BRN2 signaling disruption in different models of ASD suggests that multiple variants contributing to ASD may converge on common pathways.

The researchers hypothesize that the beta-catenin/BRN2 transcriptional cascade is a key pathway that precisely regulates NPC proliferation and differentiation during mouse and human brain development and that its dysregulation may result in at least some aspects of ASD. To address this hypothesis, Wynshaw-Boris and his team performed studies on NPCs derived from iPSC lines of one ASD patient with early brain overgrowth and one unaffected individual. This resulted in the identification of several genes and pathways that contribute to the above-mentioned phenotypes².

In the current project, the researchers plan to validate these findings and identify additional downstream pathways that are directly regulated by beta-catenin and BRN2 in humans. Such studies will include performing RNA-seq and ChIP-seq (utilizing antibodies to beta-catenin, BRN2, and relevant histone modifications consistent with activation and suppression of transcription) on NPCs derived from iPSC lines of an additional individual with ASD and an unaffected individual.