Browsing by Subject "Epithelial-Mesenchymal Transition"
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Item Pumilio Regulates the Epithelial-Mesenchymal Transition and Gastrulation During Zebrafish Development(2013-05-13) Damoulis, Vanessa Ann; Castrillon, Diego H.; Amatruda, James F.; Johnson, Jane E.; Buszczak, MichaelThe pumilio family of RNA binding proteins act as translational repressors to control developmental patterning events of invertebrates, germline stem cell maintenance, and neuronal growth through deadenylation, inhibition of translational elongation, and allow access of microRNAs to their targets. pumilio proteins have yet to be identified and functionally characterized in the zebrafish, Danio rerio. Here, three putative pumilio homologs in zebrafish are identified by their characteristic PUF (pumilio and FBF) binding domains and found to be expressed during early development and enriched in the immature oocytes of the adult ovary. Loss of each homolog results in developmental defects, arising from improper formation of the shield and dorsal organizer structures during the first steps of gastrulation. Gastrulation events necessitate both proper patterns of gene signaling and cell motility, as gained by epithelial-to-mesenchymal transitions (EMT), to occur. In pum1 morphants, both the presentation of wild-type signaling gradients and EMT events are inhibited. Through in silico and in vivo analysis, acvr1b, an Activin receptor, was identified as a target for pum1. acvr1b assists in patterning the gastrulating embryo and, through control of miR-200a expression, inhibits EMT events. Thus, pum1 through its direct translational repression of acvr1b is able to modulate levels of miR-200a and control both patterning and EMT events in the early vertebrate embryo.Item Regulation of Cardiac Fibroblast and Coronary Vascular Smooth Muscle Development by Platelet Derived Growth Factor Receptors(2013-05-31) Smith, Christopher Lacey; Tallquist, Michelle D.; MacDonald, Raymond J.; Olson, Eric N.; Chen, Zhijian J.Coronary vascular smooth muscle cells (cVSMC) and cardiac fibroblasts are essential for coronary artery development and are important mediators of myocardial pathogenesis. These cells form when a subset of epicardial cells undergoes an epithelial-to-mesenchymal transition (EMT) and migrates into the myocardium. The pathways and mechanisms regulating epicardial derived cell (EPDC) development remain largely unknown. Using mice with epicardial specific deletions of the PDGF receptors, I discovered that these receptors control EPDC fate and epicardial EMT. I demonstrated that each receptor was required for development of a unique epicardial derivative, PDGFRα for cardiac fibroblasts and PDGFRβ for cVSMC. I also found that deletion of both PDGF receptors led to a complete loss of EPDCs caused by a failure in cell exit from the epicardium. This defect resulted from decreased expression of genes involved in the EMT process and continued epithelial gene expression. Finally, I showed that Sox9, an SRY-related transcription factor, is a critical downstream mediator of PDGF signaling. This body of work establishes PDGF signaling as a key EMT regulatory pathway and suggests a novel role for Sox9 in regulating EPDC development.