MET receptor tyrosine kinase and the development of forebrain circuits

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Human genetic studies have established MET as a prominent risk gene for autism spectrum disorder, a highly heritable psychiatric disorder with disrupted ontogeny of neural connectivity. MET protein is a receptor tyrosine kinase that is tightly regulated during early brain development, peaks at a period of rapid neurite growth and synaptogenesis, and is precipitously down-regulated prior to neuronal maturation. The goal of this project is to elucidate the nature of the time-delimited signaling by investigating how it regulates key brain development events, including synaptogenesis, maturation, circuit connectivity and refinement. Preliminary results from the PI's laboratory reveal that disruption of MET signaling in mice results in altered cortical interlaminar excitatory connectivity, aberrant neuronal morphology and maturation of glutamatergic synapses, as well as impaired circuit connectivity indicative of defective synapse pruning and circuit refinement. Using a controllable transgenic mouse model created in the lab of the PI, this research team recently found that MET activation engages the Rho family small GTPases, Cdc42 and Rac1, and leads to inhibition of the actin depolymerizing factor cofilin, processes that are critical for dendritic spine morphogenesis and excitatory synapse development. This has led to the central hypothesis that MET signaling promotes early dendritic spine morphogenesis, while its down-regulation is required for dendritic spine and glutamatergic synapse maturation later in brain development. In this application, the research group brings together an interdisciplinary team and takes an integrated approach combining neuroanatomy, molecular genetics, in vivo two photon imaging, and patch clamp electrophysiology combined with laser scanning photostimulation for circuit mapping to test the following hypotheses: 1) developmental down-regulation of MET expression is required for normal glutamatergic synapse maturation ; 2) persistent MET signaling impairs developmental synapse pruning and refinement cortical circuit connectivity; and 3) disrupted MET signaling and the resulting change in forebrain developmental trajectory alter mouse behavior. Impact: It is anticipated that successful completion of these proposed studies will define an in-depth, mechanistic, and multifaceted role of MET in neural development and establishment of functional connectivity in the developing forebrain. These mechanisms collectively may be unique to MET, and may illuminate novel interventions in autism by targeting the temporal profiles of glutamatergic synapse development in specific brain circuits.