|ZFIN ID: ZDB-PUB-130410-33|
|Source:||Arterioscler. Thromb. Vasc. Biol. 33(6): 1280-6 (Journal)|
|Registered Authors:||Lin, Shuo|
|Keywords:||Cbl-interacting protein of 85K, epidermal growth factor receptor, SH3-domain GRB2-like 3, vascular lumen zebrafish|
|PubMed:||23539215 Full text @ Arterioscler. Thromb. Vasc. Biol.|
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.
Approach and Results—Sh3gl3 and its binding partner, Cbl-interacting protein of 85K (Cin85), together regulate endocytosis and were expressed in the developing vasculature. Morpholino (MO) 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 MOs 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.