Epicardial development is a complex process that involves tightly regulated coordination of concurrent cellular behaviors ranging from sheet migration to secretion. The regulation of these behaviors is poorly understood, and epicardial cell biological studies will improve the understanding of heart development and subsequent function. Here, a novel small organic molecule screening methodology of epicardial behaviors is used to elucidate regulatory relationships governing this developmental program. As proof-of-principle, a novel signaling relationship was identified in which TGFβ and BMP signal cascades cooperatively regulate epicardial sheet migration. It is further demonstrated here that epicardial cells participate in a newly identified cellular behavior: regulated cell movement through autocrine extracellular matrix (ECM) deposition. The studies identify two novel regulators of autocrine ECM deposition, Bves and NDRG4. Additionally, we demonstrate that Bves regulates cell surface trafficking of the focal adhesion component β1-integrin through an interaction with VAMP3, a v-SNARE recycling endosome component. These studies in combination with previous work indicate that Bves functions in epicardial cells and globally to traffic adhesion components to the cell surface. This positions Bves as a general regulator of cell-cell and cell-matrix adhesion. Taken together, these studies elucidate regulation of epicardial cell behaviors, reveal a novel epicardial behavior, and suggest a global mechanism for Bves diverse effects of development and disease.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-01252012-155505 |
| Date | 26 January 2012 |
| Creators | Cross, Emily Elizabeth |
| Contributors | Alissa Weaver, David Bader, H. Scott Baldwin, Sandra Zinkel, Matthew Tyska |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-01252012-155505/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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