Neural Networks in Autism: Linking MET Polymorphisms and Polyaromatic Hydrocarbons

A significant challenge in improving the clinical manifestations of autism spectrum disorder (ASD) is placing descriptive findings of genetic and environmental risk in a functional context.  This can be accomplished by determining the underlying cellular and molecular disruptions that lead to ASD cognitive and behavioral phenotypes, and the non-genetic environmental factors that contribute to spectrum cause and clinical heterogeneity.  This presentation will illustrate the power of a translational research strategy to generate an emerging picture that includes improved definition of biological mechanisms and emergent concepts of clinical heterogeneity.  Our human genetic studies have led to the discovery of a novel ASD risk gene, the MET receptor tyrosine kinase.  The only known growth factor ligand for MET is hepatocyte growth factor (HGF).  MET promoter variants, ASD-relevant transcriptional regulators, including FOXP2, and specific pollutants, such as benzo-a-pyrene, all reduce the levels of MET gene expression.  Developmental regulation of expression is functionally essential, as MET expression is reduced in postmortem brain samples from subjects with ASD compared to control samples.  How does MET participate in increasing ASD risk?  Our studies on the biological significance of MET in the brain have revealed a number of important functions that relate to ASD risk, including 1) a gene for which expression is among the most highly restricted in the primate cerebral cortex, particularly in ASD-relevant circuits; 2) regulation of axonal and dendritic growth, and spine and synapse maturation; 3) a dominant effect of a graded decrease in Met expression that causes dramatic changes in local excitatory connectivity in the neocortex; 4) a dominant effect of the MET ASD risk variant that correlates with disrupted circuitry that functions to process emotional faces in the human; 5) enrichment of the MET risk variant in children with ASD and co-occurring gastrointestinal disorders, reflecting important pleiotropic functions of MET outside of the brain.  These data provide a significant foundation for future studies that will lead to a better understanding of pathogenic mechanisms and clinical heterogeneity of ASD.