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    MED23: a Mediator subunit's role in global gene transcription, regulation of craniofacial development and WNT signaling.

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    Bhatt_ku_0099D_13072_DATA_1.pdf (3.066Mb)
    Issue Date
    2013-12-31
    Author
    Bhatt, Shachi Bhasker
    Publisher
    University of Kansas
    Format
    268 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Anatomy & Cell Biology
    Rights
    Copyright held by the author.
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    Abstract
    Expression of genes at the right time and place is crucial during adult homeostasis as well as embryonic development. Multicellular organisms regulate this spatiotemporal expression of genes by employing tissue specific transcription factors which bind to enhancer and repressor elements distant from the gene transcription start site. In embryonic development, most of the research understanding cell differentiation has focused on identifying such tissue specific transcription factors. What we do not understand clearly, is how these transcription factors that bind so far away from the gene promoter site influence the decision of RNA Pol II to transcribe or not transcribe. A recent discovery of a mega-dalton protein complex, called Mediator, has begun to answer this question. Mediator complex physically interacts with RNA Pol II and general transcription factors on one side and with transcription factors bound to enhancer/repressor sites on the other side. Mediator has thus been shown to act as a bridge that relays information between the transcription factors and RNA Pol II machinery and thus regulate gene expression. The various subunits of Mediator complex have been shown to interact with distinct transcription factors to regulate expression of specific genes. In this work, I describe the role of one such Mediator subunit, MED23. The role of MED23 during mammalian embryonic development was identified through a forward genetics screen done in the lab. Loss of med23 leads to mid-gestational lethality in mice embryos along with defects in craniofacial, neural and vascular development. We currently do not know the exact cause for embryonic lethality in med23 mutant embryos, but my results indicate that MED23 is crucial for endothelial cell-cell junction formation at E9.5, defects in which have previously been shown to affect embryonic survival. Specifically the formation of adherens and tight junctions between endothelial cells is affected in med23 mutant embryos. Analysis of neuronal defects in med23 mutant embryos suggests that MED23 is required during various steps of cranial placode development and this is regulated by MED23-mediated regulation of canonical WNT signaling. How and why loss of MED23 leads to defects in these specific tissues is currently unknown, but work with conditional mutant analysis as well as transcription factor-binding screens are underway to figure this out. My work thus highlights a unique link between general transcription co-factor, Mediator, and its subunit MED23 with development of neural, vascular and craniofacial tissues and a crucial signaling pathway, WNT signaling.
    URI
    http://hdl.handle.net/1808/19563
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    785-864-8983
    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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