title: Hyaluronic acid receptor Stabilin-2 regulates Erk phosphorylation and arterial--venous differentiation in zebrafish.
abstract: The hyaluronic acid receptor for endocytosis Stabilin-2/HARE mediates systemic clearance of multiple glycosaminoglycans from the vascular and lymphatic circulations. In addition, recent in vitro studies indicate that Stab2 can participate in signal transduction by interacting with hyaluronic acid (HA), which results in Erk phosphorylation. However, it is not known whether Stab2 function or HA-Stab2 signaling play any role in embryonic development. Here we show that Stab2 functions in a signal transduction pathway regulating arterial-venous differentiation during zebrafish embryogenesis. Stab2 morpholino knockdown embryos (morphants) display an absence of intersegmental vessels and defects in the axial vessel formation. In addition, Stab2 morphants show defects in arterial-venous differentiation including the expansion of venous marker expression. Simultaneous knockdown of Stabilin-2 and Has2, an HA synthetase, results in a synergistic effect, arguing that HA and Stab2 interact during vasculature formation. Stab2 morphants display reduced Erk phosphorylation in the arterial progenitors, which is a known transducer of VEGF signaling, previously associated with arterial-venous differentiation. In addition, VEGF signaling acts as a negative feedback loop to repress stab2 expression. These results argue that Stab2 is involved in a novel signaling pathway that plays an important role in regulating Erk phosphorylation and establishing arterial-venous identity.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Rost
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America ; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center/University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Saulius
authors.initials: S
authors.lastname: Sumanas
mesh_terms: D000818:Animals; D001158:Arteries / Q000196:embryology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D014680:Veins / Q000196:embryology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D029961:Zebrafish Proteins; D006820:Hyaluronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases