Expression and Function of the ASD-Associated Met Receptor Tyrosine Kinase During Mammalian Forebrain Development

Abstract

For two principle reasons, the transmembrane Met receptor tyrosine kinase has emerged as an important molecular target for study in the developing forebrain: 1) it regulates a variety of neurodevelopmental processes in vitro, including cell migration, neurite outgrowth, and synaptogenesis, and 2) replicate human genetic studies have demonstrated associations of allelic MET variants with autism spectrum disorders (ASD). One particular MET variant reduces transcriptional efficiency in vitro, and MET protein levels are reduced ~2-fold in postmortem ASD neocortex, implicating reduced MET signaling in the etiology of this neurodevelopmental disorder. To begin to clarify the neurodevelopmental influences of MET signaling in vivo, we comprehensively mapped Met mRNA and Met protein expression in the mouse forebrain throughout perinatal and postnatal development. In situ hybridization revealed Met transcript expression throughout the cerebral cortex and in limbic structures including the hippocampus, amygdala, and septum. Met immunohistochemistry showed Met protein enrichment in long-projecting axons of neurons within these forebrain structures during peak periods of axon arborization and synaptogenesis over the first two postnatal weeks. Comparative immunohistochemical mapping in the nonhuman primate macaque demonstrated conserved temporal and subcellular patterns of Met expression. Spatially, Met protein expression was conserved in subcortical limbic structures, but highly restricted neocortically within the cingulate gyrus and temporal lobes. Collectively, these data implicate Met signaling in the wiring of cortical and limbic circuits, which govern species-typical social and emotional behaviors that are atypical in ASD. Moreover, they predict circuit-level, presynaptic consequences of Met signaling disruption. Single-cell morphometric analyses in a forebrain-specific conditional Met knockout mouse confirmed this, revealing discrete effects on dendrite and dendritic spine morphology. In summary, these studies reveal a role for Met signaling in the development of forebrain connectivity and further our understanding of selective circuit vulnerabilities in ASD. Future efforts will employ electrophysioligical and biochemical/bioinformatics approaches to elucidate the functional consequences of developmental Met signaling disruptions in the forebrain.