Examining an extracellular matrix regulator required for cardiovascular development (2016–2019)
Abstract:
The cardiovascular system provides nutrients and removes waste from every cell in the body. Defects affecting its structure and function are often fatal. The endothelium is a major contributor to the cardiovascular system. Endothelial cells make up the blood vessels and internal structures of the heart, including the cardiac valves. Given this common origin, the heart and vessels share common genetic regulators and we have discovered one such regulator: tmem2. Tmem2 was discovered in a forward genetic screen in zebrafish for its role in cardiac valve development. We now show that it is also required for angiogenesis. Tmem2 is a transmembrane protein and preliminary data shows that it functions in the extracellular matrix (ECM). tmem2 mutants have excess ECM and, remarkably, mutant phenotypes are rescued by degrading the ECM. Intracellular signaling is reduced in endothelial cells in the absence of tmem2, supporting a model whereby Tmem2 assists to prune the ECM and, in its absence, excess ECM prevents ligand-mediated signaling, causing cardiovascular defects. This project grant will investigate the role of Tmem2 in mammalian development. We have created numerous Tmem2 conditional mouse lines and will determine the tissue and timing requirement for tmem2 in the mouse cardiovascular system. A gain-of-function model using a secreted functional Tmem2 fragment will be created and genetic interaction experiments will investigate signaling activity. Finally, the role of Tmem2 in a mouse macular degeneration model and a myocardial infarction model will be examined. This research will provide valuable insights into the poorly understood role of the ECM in development and disease and generate a model to test the therapeutic potential of tuning the ECM during cardiovascular development and maintenance.
