• About
    • Login
    View Item 
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of Institutional RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsDepartmentThis CollectionBy Issue DateAuthorsTitlesSubjectsDepartment

    My Account

    LoginRegister

    Expression and Function of the ASD-Associated Met Receptor Tyrosine Kinase During Mammalian Forebrain Development

    Judson, Matthew C.
    : https://etd.library.vanderbilt.edu/etd-03302010-112242
    http://hdl.handle.net/1803/11762
    : 2010-04-12

    Abstract

    For two principle reasons, the transmembrane Met receptor tyrosine kinase has emerged as an important molecular target for study in the developing forebrain: 1) it regulates a variety of neurodevelopmental processes in vitro, including cell migration, neurite outgrowth, and synaptogenesis, and 2) replicate human genetic studies have demonstrated associations of allelic MET variants with autism spectrum disorders (ASD). One particular MET variant reduces transcriptional efficiency in vitro, and MET protein levels are reduced ~2-fold in postmortem ASD neocortex, implicating reduced MET signaling in the etiology of this neurodevelopmental disorder. To begin to clarify the neurodevelopmental influences of MET signaling in vivo, we comprehensively mapped Met mRNA and Met protein expression in the mouse forebrain throughout perinatal and postnatal development. In situ hybridization revealed Met transcript expression throughout the cerebral cortex and in limbic structures including the hippocampus, amygdala, and septum. Met immunohistochemistry showed Met protein enrichment in long-projecting axons of neurons within these forebrain structures during peak periods of axon arborization and synaptogenesis over the first two postnatal weeks. Comparative immunohistochemical mapping in the nonhuman primate macaque demonstrated conserved temporal and subcellular patterns of Met expression. Spatially, Met protein expression was conserved in subcortical limbic structures, but highly restricted neocortically within the cingulate gyrus and temporal lobes. Collectively, these data implicate Met signaling in the wiring of cortical and limbic circuits, which govern species-typical social and emotional behaviors that are atypical in ASD. Moreover, they predict circuit-level, presynaptic consequences of Met signaling disruption. Single-cell morphometric analyses in a forebrain-specific conditional Met knockout mouse confirmed this, revealing discrete effects on dendrite and dendritic spine morphology. In summary, these studies reveal a role for Met signaling in the development of forebrain connectivity and further our understanding of selective circuit vulnerabilities in ASD. Future efforts will employ electrophysioligical and biochemical/bioinformatics approaches to elucidate the functional consequences of developmental Met signaling disruptions in the forebrain.
    Show full item record

    Files in this item

    Icon
    Name:
    MattJudson_ETD.pdf
    Size:
    26.09Mb
    Format:
    PDF
    View/Open

    This item appears in the following collection(s):

    • Electronic Theses and Dissertations

    Connect with Vanderbilt Libraries

    Your Vanderbilt

    • Alumni
    • Current Students
    • Faculty & Staff
    • International Students
    • Media
    • Parents & Family
    • Prospective Students
    • Researchers
    • Sports Fans
    • Visitors & Neighbors

    Support the Jean and Alexander Heard Libraries

    Support the Library...Give Now

    Gifts to the Libraries support the learning and research needs of the entire Vanderbilt community. Learn more about giving to the Libraries.

    Become a Friend of the Libraries

    Quick Links

    • Hours
    • About
    • Employment
    • Staff Directory
    • Accessibility Services
    • Contact
    • Vanderbilt Home
    • Privacy Policy