[ST6]: Met modulates cortical circuit development in vivo

The Met receptor tyrosine kinase has been shown in vitro to regulate neurodevelopmental processes including cell migration, neurite outgrowth, and synaptogenesis, which serve to establish appropriate neuronal connectivity. In addition, a functional promoter variant of the human MET gene was recently discovered to be a significant risk factor for autism spectrum disorder (ASD). ASD and other neurodevelopmental disorders have been postulated to share in common disruptions in cortical connectivity. We thus examined Met signaling in the context of cortical circuit development in vivo. First, we developmentally mapped cortical Met expression in wild type mice using complementary immunoblotting and immunohistochemical approaches.We found that: (1) Met expression peaks between postnatal days 7 and 14, coinciding with principle periods of neurite outgrowth and synaptogenesis, and (2) during the peak period of expression, Met protein is localized to the dendrites and axons of projection neurons. We next used an Emx1cre/loxP approach to conditionally ablate Met signaling in all cells arising from the dorsal pallium, including cortical projection neurons. Quantitative morphometric analyses of pyramidal dendrites revealed an approximately 20% increase in dendritic protrusions in conditional null mice as compared to littermate controls, suggesting aberrant synaptic maturation in these mice. Consistent with this, immunoblotting of synapseenriched cortical fractions showed selective alterations in PSD-95 and phosphorylated CaMKII. Collectively, these findings strongly implicate Met signaling in the development of cortical circuitry in vivo and may provide insight into the etiologies of ASD and other neurodevelopmental disorders. Supported by: Marino Autism Research Institute, NIMH Grant MH080759 and NICHD Grant HD15052