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

Abstract

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

Social Origins of Developmental Risk for Mental and Physical Illness

“…One week separated monkeys paired with an experienced mother at 25 d of age displayed completely normal social behavior as they grew up, whereas pairing at 35 d of age only partially restored normal social behavior and those paired at 45 d showed virtually no restoration of normal social behavior (Knudsen et al, 2006;O'Connor and Cameron, 2006). These studies in the monkey provide clear evidence that the timing of stress exposure, or the interventions to remediate it, is a significant factor in determining the long-term consequences of ELS.…”

“…These include increased anxious behaviors, aberrant attachment patterns, and changes in central neurotransmitter levels, including serotonin, norepinephrine, and dopamine, adrenal axis regulation, and social behavior and brain structure in the long term (Harlow and Zimmerman, 1959;Harlow and Suomi, 1974;Suomi et al, 1975;Coplan et al, 1998;Sánchez et al, 2001;Winslow, 2005;Knudsen et al, 2006;O'Connor and Cameron, 2006;Sabatini et al, 2007;Spinelli et al, 2009Spinelli et al, , 2010de Campo et al, 2017). We focus here on limbic circuitry (Fig.…”

“…Likewise, the ability of an intervention (adoption by an attentive mother) to remediate aberrant behaviors resulting from ELS is also dependent upon the timing of the intervention (Knudsen et al, 2006;O'Connor and Cameron, 2006). One week separated monkeys paired with an experienced mother at 25 d of age displayed completely normal social behavior as they grew up, whereas pairing at 35 d of age only partially restored normal social behavior and those paired at 45 d showed virtually no restoration of normal social behavior (Knudsen et al, 2006;O'Connor and Cameron, 2006).…”

“…Impact of the timing of exposure on brain and behavioral responses to stress was explored in a series of studies with monkeys (Knudsen et al, 2006;O'Connor and Cameron, 2006;Sabatini et al, 2007;de Campo et al, 2017). Rhesus macaques were reared from 1 week of age with their mothers in social housing with penmates of various ages and both sexes.…”

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

“…As model 4 (Figure 5d) shows, miR-3666 can play an "enemy" role to FOXP2 by repressing FOXP1 and removing its inhibitory effect on CNTNAP2 or it may inhibit FOXP1 expression and affect the modulatory roles of FOXP2 that requires FOXP1-FOXP2 dimerization. FOXP2 and miR-3666 can also jointly affect the levels of common targets MET (MET receptor tyrosine kinase), TCF4, SNAP25 (synaptosomal-associated protein of 25 kDa) and PTPN11, which are candidate genes for ASD [103][104][105][106][107]. PAX6 regulation by miR-3666 is not only important to maintain the levels of FOXP2 but also to prevent the development of autism and related disorders, as PAX6 is also a candidate gene for ASD [108].…”