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

Authors

  • Matthew C. Judson,

    1. Graduate Program in Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37203
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    • The first two authors contributed equally to this work.

  • Mica Y. Bergman,

    1. Graduate Program in Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37203
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    • The first two authors contributed equally to this work.

  • Daniel B. Campbell,

    1. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37203
    2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37203
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  • Kathie L. Eagleson,

    1. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37203
    2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37203
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  • Pat Levitt

    Corresponding author
    1. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee 37203
    2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37203
    • Zilkha Neurogenetic Institute, Keck School of Medicine of USC, 1501 San Pablo Street, Los Angeles, CA 90089-2821
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Abstract

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. J. Comp. Neurol. 513:511–531, 2009. © 2009 Wiley-Liss, Inc.

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