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Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.

Benesh EC, Miller PM, Pfaltzgraff ER, Grega-Larson NE, Hager HA, Sung BH, Qu X, Baldwin HS, Weaver AM, Bader DM
Mol Biol Cell. 2013 24 (22): 3496-510

PMID: 24048452 · PMCID: PMC3826988 · DOI:10.1091/mbc.E12-07-0539

Directional cell movement is universally required for tissue morphogenesis. Although it is known that cell/matrix interactions are essential for directional movement in heart development, the mechanisms governing these interactions require elucidation. Here we demonstrate that a novel protein/protein interaction between blood vessel epicardial substance (Bves) and N-myc downstream regulated gene 4 (NDRG4) is critical for regulation of epicardial cell directional movement, as disruption of this interaction randomizes migratory patterns. Our studies show that Bves/NDRG4 interaction is required for trafficking of internalized fibronectin through the "autocrine extracellular matrix (ECM) deposition" fibronectin recycling pathway. Of importance, we demonstrate that Bves/NDRG4-mediated fibronectin recycling is indeed essential for epicardial cell directional movement, thus linking these two cell processes. Finally, total internal reflectance fluorescence microscopy shows that Bves/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface, providing a molecular mechanism of motility substrate delivery that regulates cell directional movement. This is the first evidence of a molecular function for Bves and NDRG4 proteins within broader subcellular trafficking paradigms. These data identify novel regulators of a critical vesicle-docking step required for autocrine ECM deposition and explain how Bves facilitates cell-microenvironment interactions in the regulation of epicardial cell-directed movement.

MeSH Terms (20)

Animals Autocrine Communication Cell Adhesion Molecules Cell Membrane Cell Movement Chlorocebus aethiops COS Cells Embryo, Mammalian Endosomes Extracellular Matrix Fibronectins Gene Expression Regulation, Developmental Mice Mice, Inbred C57BL Muscle Proteins Nerve Tissue Proteins Pericardium Primary Cell Culture Signal Transduction Transport Vesicles

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