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Investigation of the role of MET kinase in autism

Ted Dawson, M.D., Ph.D.
Johns Hopkins University School of Medicine

Genetic studies have linked several new genes to increased risk of autism. The challenge, however, is in understanding how mutations in these genes disrupt neural development and cause the disorder. Ted Dawson and his colleagues at Johns Hopkins University plan to undertake this task for the signaling protein known as the MET receptor.

When it binds a signaling molecule, the MET receptor activates a pathway that regulates cell shape during the morphogenetic movements of early development and the metastasis of cancers. In the past few years, scientists have found that the MET receptor can also influence the shape of neurons, such as where and when the cells form signaling sites known as synapses. For example, the MET receptor can induce the branching of neurons to create more or stronger synapses and the clustering of proteins at these structures.

Several lines of evidence indicate that the neurons do not signal to each other properly in people with autism. Most genes linked to autism regulate synapse formation and activity, and the abnormal patterns of activity in autistic brains also suggest that neurons are not making the right connections with each other. In 2006, one research team linked some cases of autism to a mutation in the MET receptor gene that reduces the amount of protein made. Dawson and colleagues propose that the low expression of the MET receptor may impair synapse formation and the wiring of neurons in the brain, leading to the social, language and behavioral deficits associated with autism.

To test this hypothesis, the researchers first plan to measure the activity of the MET receptor in people with autism to confirm that reduced gene expression correlates with low signaling in the cell. They plan to then study what happens in cultured neurons that have reduced MET signaling: the neurons may not branch often enough and form the right connections, for instance, or the neural stem cells may not be incorporated into the intricate structure of the brain, leading to fewer or mis-wired cells. The researchers intend to investigate the specific mechanisms by which reduced MET signaling leads to disruptions in neuronal signaling, hoping to link particular proteins in the signaling pathway to processes that could become targets for autism therapy.


proposalCENTRAL #SFARI-07-11