Myocyte-myocyte interaction is essential for heart development and function. We have discovered a novel family of transmembrane proteins (Bves/Popeye) that has a highly conserved protein sequence. Our work demonstrates that Bves acts as a cell adhesion molecule and is essential for maintenance of cell-cell interaction. Additionally, Bves is one of the first proteins to localize to points of cell-cell contact. In heart development, Bves is first present around the entire myocyte membrane at the onset of development but is later restricted to the intercalated disc. From these data, we predict that Bves plays an essential and early role in the cascade of events regulating adhesion during cardiac morphogenesis and in the generation of the disc. We have identified two novel interaction domains within the protein that are critical for Bves function and potentially for heart development including generation of the intercalated disc. First, a specific domain that regulates Bves-Bves intracellular interaction has been defined. Deletion or mutation of this domain abolishes Bves-Bves interaction and leads to complete inhibition of cell-cell adhesion. Second, we have discovered that Bves interacts through its C-terminus with ZO1, an essential component of the intercalated disc. Using molecular and physiological challenges, we have determined that inhibition of Bves function destabilizes ZO1 at the cell membrane and disrupts cell junctions. From these data, we hypothesize that Bves has essential functions in myocyte adhesion during heart development and in the formation of the intercalated disc. Three interactive specific aims will test the roles of the Bves-Bves intracellular interaction domain and Bves-ZO1 interaction domain during cardiac myogenesis in vivo and in vitro. Transgenic expression of Bves mutated in these domains will determine protein function during remodeling of cardiogenic epithelium, trabeculation, compaction and formation of the intercalated disc. It is clear that aberrant cell adhesion can lead to severe heart defects and that malformation of the heart represents one of the largest and most deleterious groups of abnormalities in embryogenesis. Determining how embryonic myocytes interact is essential in understanding heart defect; in the proposed studies, we will elucidate Bves function in cardiac morphogenesis and disc formation but, in a larger sense, determine how myocyte- myocyte interaction governs heart development and function. ? ? ?
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