title: Essential role of SH3-domain GRB2-like 3 for vascular lumen maintenance in zebrafish.
abstract: OBJECTIVE
  Studying the underlying molecular mechanisms for maintaining stereotyped vascular lumen diameters should help toward a comprehensive understanding of vascular homeostasis and function. We aimed to determine the role of SH3-domain GRB2-like 3 (Sh3gl3) and its interacting pathways in dorsal aorta (DA) maintenance in zebrafish.
  
  
  RESULTS
  Sh3gl3 and its binding partner, Cbl-interacting protein of 85K (Cin85), together regulate endocytosis and were expressed in the developing vasculature. Morpholino knockdown of either gene resulted in shrinkage of the DA lumen, although artery/vein specification and the initial formation of vascular lumens were unaffected. In addition, sh3gl3 and cin85 morpholinos exerted a synergistic effect in causing the vascular phenotypes. To identify the signaling pathways in which Sh3gl3/Cin85 may participate, we screened several candidate inhibitors for their ability to induce similar circulatory defects. Chemical inhibition of the epidermal growth factor receptor and the phosphatidylinositol 3-kinase/Akt cascade led to a loss of circulation and shrunken DA in zebrafish embryos. Furthermore, inhibition of the epidermal growth factor receptor/phosphatidylinositol 3-kinase pathway showed a functional cooperation with Sh3gl3 deficiency in impairing DA lumens.
  
  
  CONCLUSIONS
  These results identify 2 new factors, Sh3gl3 and Cin85, which are essential for DA lumen maintenance, and suggest that endocytosis, possibly involving epidermal growth factor receptor and phosphatidylinositol 3-kinase, is implicated in Sh3gl3/Cin85 function.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D023421:Models, Animal; D011485:Protein Binding; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology; D014654:Vascular Patency / Q000502:physiology*; D015027:Zebrafish; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D066246:ErbB Receptors
keywords: Cbl-interacting protein of 85K; SH3-domain GRB2-like 3; epidermal growth factor receptor; vascular lumen; zebrafish