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    FGF Signaling During Gastrulation and Cardiogenesis

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    Author
    Bobbs, Alexander Sebastian
    Issue Date
    2012
    Keywords
    Development
    FGF signaling
    Gastrulation
    RNA
    Molecular & Cellular Biology
    Cardiogenesis
    Chicken
    Advisor
    Antin, Parker B.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    An early event in animal development is the formation of the three primary germ layers that define the body plan. During gastrulation, cells migrate through the primitive streak of the embryo and undergo changes in morphology and gene expression, thus creating the mesodermal and endodermal cell layers. Gastrulation requires expression of Fibroblast Growth Factor (FGF), Wnt, and Platelet-Derived Growth Factor (PDGF). Embryos treated with FGF inhibitors fail to gastrulate, as cell migration is completely halted. During gastrulation, 44 microRNAs are expressed in the primitive streak of G. gallus embryos, and six (microRNAs -let7b, -9, -19b, -107, -130b, and -218) are strongly upregulated when FGF signaling is blocked. The abundance of these six FGF-regulated microRNAs is controlled at various stages of processing: most are regulated transcriptionally, and three of them (let7b, 9, and 130b) are blocked by the presence of Lin28B, an RNA-binding protein upregulated by FGF signaling. These microRNAs target various serine/threonine and tyrosine kinase receptors. We propose a novel pathway by which FGF signaling downregulates several key microRNAs (partially through Lin28B), upregulating gene targets such as PDGFRA, which permits and directs cell migration during gastrulation. These findings add new layers of complexity to the role that FGF signaling plays during embryogenesis. FGF signaling is also required for the formation of the heartfields, and has an overlapping pattern of expression with BMP (Bone Morphogenetic Protein). A microarray experiment using inhibitors of FGF and BMP found that thousands of genes in pre-cardiac mesoderm are affected by FGF signaling, BMP signaling, or a cooperative effect of the two. The promoter regions of similarly regulated genes were queried for over-represented transcription factor binding sites or novel DNA motifs. Cluster analysis of over-represented sites determined candidate transcriptional modules that were tested in primary cardiac myocyte and fibroblast cultures. About 75% of predicted modules in FGF-upregulated genes proved to be functional enhancers or repressors. Functional enhancers among FGF-upregulated genes contained clusters of CdxA and NFY sites, and increased transcription in the presence of a constitutively active FGF receptor.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Molecular & Cellular Biology
    Degree Grantor
    University of Arizona
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