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

Graduate Program in Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA.
The Journal of Comparative Neurology (Impact Factor: 3.23). 04/2009; 513(5):511-31. DOI: 10.1002/cne.21969
Source: PubMed


The establishment of appropriate neural circuitry depends on 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 the social and emotional dimensions of behavior.

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Available from: Daniel Campbell, Jul 15, 2014
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    • "MET is a gene encoding a protein within the ERK/PI3 signaling pathway, and is closely regulated during the development of excitatory neurons during synapse formation in regions of the brain important for social cognition (Levitt and Campbell, 2009). Variations in MET have been linked to increased risk for ASD (Campbell et al., 2010), and in animal models have been associated with developmental abnormalities consistent with ASD phenotypes (Judson et al., 2009). Alleles of rs158830, located within the promoter region of MET, have been of particular interest because of their effects on transcription and protein expression of MET. "
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    Frontiers in Human Neuroscience 10/2013; 7:733. DOI:10.3389/fnhum.2013.00733 · 3.63 Impact Factor
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    • "The Met receptor, long known to be present (at low levels) and active in synapses of the mature brain (Tyndall and Walikonis, 2006) has now been found to be more highly expressed, before most synaptogenesis occurs, in extending forebrain axons of the developing mouse brain. Judson et al. (2009) demonstrated peak Met expression by Western blot at birth in the developing mouse brain; the period at which neurons are finished migrating and are actively extending axons and dendrites. These levels declined during synaptogenesis to low, adult baseline levels (Judson et al., 2009). "
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    Frontiers in Human Neuroscience 10/2013; 7:671. DOI:10.3389/fnhum.2013.00671 · 3.63 Impact Factor
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    • "This releases β-catenin for nuclear signaling and, furthermore, by limiting cell-cell adhesion, it promotes cellular motility [21,67,68]. Cellular motility is crucial for interneuron migration, dendrite extension and synapse formation, and consequently, these processes are reduced by genetic disruption of MET[69,70]. HGF-MET signaling, therefore, contributes to neuronal differentiation, to development of cerebral cortex and cerebellum and to axon growth [66,69-71]. "
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