title: Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Pediatric Cardiology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Benesh
authors.forename: Paul M
authors.initials: PM
authors.lastname: Miller
authors.forename: Elise R
authors.initials: ER
authors.lastname: Pfaltzgraff
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Grega-Larson
authors.forename: Hillary A
authors.initials: HA
authors.lastname: Hager
authors.forename: Bong Hwan
authors.initials: BH
authors.lastname: Sung
authors.forename: Xianghu
authors.initials: X
authors.lastname: Qu
authors.forename: H Scott
authors.initials: HS
authors.lastname: Baldwin
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
authors.forename: David M
authors.initials: DM
authors.lastname: Bader
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002465:Cell Movement / Q000235:genetics*; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D015398:Signal Transduction; D022161:Transport Vesicles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C498789:Bves protein, mouse; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D009124:Muscle Proteins; C527709:Ndrg4 protein, mouse; D009419:Nerve Tissue Proteins
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