Functional consequences of disrupted MET signaling
Pat Levitt, Ph.D.
Gordon Shepherd, M.D., Ph.D.
University of Southern California
A number of risk genes for autism spectrum disorders have been identified, thanks to the intensive efforts of the Simons Foundation and other genetic consortia. This is just the beginning, however. A major goal of future research is to translate these genetic findings into a more in-depth understanding of how such risk, combined with environmental factors, disrupts the formation of brain architecture that leads to autism. This information is essential to designing better prevention, diagnostic and intervention strategies for the disorder.
To that end, Pat Levitt, of the University of Southern California, is leading a collaborative effort by four laboratories to understand the functional implications of mutations in the autism risk gene MET, which codes for a receptor that is involved in the wiring up of important brain circuits. The researchers’ previous study of three large collections of families with members with autism found a mutation in MET that more than doubles the risk for autism and reduces the amount of MET protein in the brains of people with the disorder. Three other research laboratories, using five different family collections around the world, have reported similar findings regarding MET as an autism risk factor. What’s more, basic research in mice has shown that altering MET expression leads to problems in the formation of synapses — the junctions between neurons — which ultimately affects the ability of the cells to communicate with each other to process complex information.
Levitt’s team is working on clinical follow-up studies to determine the correlation between the MET mutation and disrupted brain and gastrointestinal functions in autism, a project also supported by the Simons Foundation. To understand why this gene may be a key risk factor for autism, Levitt and colleagues are investigating how the MET gene controls the development of synapses in circuits that control social and emotional behaviors and learning. In addition, Levitt and his colleagues will investigate the impact of a ‘double hit’ — a genetic mutation of MET, combined with exposure to a common pollutant that by itself negatively impacts developing brain architecture. This is being done by using genetic tools and new methods for measuring neuron activity in key brain circuits that include the cerebral cortex, a structure that is responsible for complex functions, such as processing social and emotional information. Their experiments will test the popular hypothesis that in autism, local and long-range connections in the brain do not assemble properly, leading to the core behavioral features of the disorder.
The team of scientists are performing a number of studies. The development of new complex cognitive tests in mutant mice are being led by Larry Rothblat (George Washington University). Darryl Hood (Meharry Medical College) is leading the efforts involving prenatal exposure to polyaromatic hydrocarbons, a common pollutant that appears to have a negative impact on the long-term expression of both MET and another key protein, SP4, that can control MET expression. Advances in the local and long-distance circuit analyses in MET mutant mice are being led by Gordon Shepherd (Northwestern University), who has already demonstrated hyperconnectivity in local circuits. The research findings from this basic research program, the continuing clinical studies, and the additional genetic replication in new family collections, strongly support MET as a biologically and genetically relevant risk factor for autism.