Dynamic gene and protein expression patterns of the autism‐associated met receptor tyrosine kinase in the developing mouse forebrain

Abstract

The establishment of appropriate neural circuitry depends upon the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival - all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits with particular relevance to social and emotional dimensions of behavior.

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

“…Although both ERBB4 and MET activate PI3K signaling, the differential timing and patterns of expression of each of these RTKs in developing cerebral cortex (61) may account for the distinct neurodevelopmental disruptions characteristic of each disorder. We have shown that MET is enriched in neocortex, amygdala, septum, and cerebellum, regions implicated in ASD (62).…”

Corticostriatal connectivity and its role in disease

“…Carriers show atypical activation/deactivation responses to social stimuli, and reduced corticocortical connectivity 102 . In human, monkey, and mouse brains, MET is expressed in IT but not PT neurons 103 . In Met conditional knockout mice, intracortical excitatory circuits show abnormally increased strength (hyperconnectivity), specifically for IT-CStr and not PT-CPn neurons 104 , and altered dendritic morphology of striatal spiny neurons 105 .…”

Recent Advances in the Genetics of Vocal Learning

“…Konopka et al, 2012). Though protein levels are dynamic during development, a peak of expression coincides with increased development of neurites and synapse formation, suggesting a role for MET in neuronal connectivity (Judson, Bergman, Campbell, Eagleson, & Levitt, 2009). MET is expressed in axon tracts of projection neurons of the neocortex, including those that descend into the striatum, consistent with the hypothesis that MET is a factor in development of neural circuits, which when perturbed, leads to symptoms of ASD and language impairment.…”