The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain

摘要

The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated inudthe structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, whichudplays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events.udVery little is known, however, on how MET signaling engages distinct cellular events to collectively affectudbrain development in ASD-relevant disease domains. Here, we show that MET protein expression isuddynamically regulated and compartmentalized in developing neurons. MET is heavily expressed inudneuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 toudpromote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of METudsignaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functionaludmaturation. In contrast, prolonged activation of MET represses the formation and functionaludmaturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in theuddeveloping prefrontal projection neurons disrupts the local circuit connectivity made onto theseudneurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronaludgrowth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling mayudlead to pathological changes in forebrain maturation and connectivity, and thus contribute to theudemergence of neurological symptoms associated with ASD.