Functional consequences of disrupted MET signaling
Pat Levitt, Ph.D.
Children's Hospital Los Angeles
Common variation in the human genome accounts for more than half of autism diagnoses. On an individual gene basis, however, common variation may have small effects in terms of autism risk. Researchers in the field are therefore challenged with understanding the impact of common variation on developing neurobiological circuits that are implicated in the functional symptoms at the core of autism.
There are few examples of replicated common variants in identified genes that are also functional in nature. The MET gene encodes a growth factor receptor that is enriched at developing synapses, or neuronal junctions, of circuits involved in social and emotional functions. The autism risk variant in MET is located in the region of the gene that controls the levels of gene expression. Protein and gene expression are reduced both in individuals with autism and those with Rett syndrome, a syndromic disorder that includes a high proportion of individuals with autism. Given these facts, Pat Levitt and his colleagues had a central goal of discovering the functional impact of altering levels of MET expression through genetic and environmental means.
Behavioral studies in genetic models demonstrated that reduction of MET results in reduced motor activity, poorer emotional regulation and reduced social exploration. Electrophysiological studies on local circuits in the neocortex and hippocampus showed that reducing or increasing levels of MET expression disrupts the timing of circuit maturation. The findings show that disturbances in the way that excitatory synapses mature during development can result in both short-term and long-term changes in how circuits respond to activation and even how they process information. One way to control of levels of MET expression in people is through the functional genetic variants in the control regions of genes.
There is increasing interest in the field to determine the environmental risk factors that combine with genetic susceptibility for autism to impact gene expression, and ultimately brain development. Levitt and his team combined MET genetic changes and air pollutant exposures, resulting in much larger changes in gene expression than with either individually. These data are consistent with human population studies that implicate the autism risk variant in MET as a mediator of the impact of air pollution exposure on risk. Together, the group’s studies provide new opportunities for determining how factors that impact human neurobiology through altering MET signaling affect autism risk, and provide additional targets for strategies to improve functional outcomes.
Award #: 137273