Abstract
Angiogenesis is spatially and temporally orchestrated by a myriad of signaling pathways, including the Notch signaling pathway. Here, we identified UXT as an evolutionarily conserved and developmentally expressed protein, indispensable for intersegmental vessel (ISV) formation in zebrafish. Deficiency of UXT in zebrafish embryos results in shorter ISVs, loss of tip cell behavior, and impairment of endothelial cell migration and division. Significantly, UXT attenuates the expression of the Notch-responsive genes in vitro and in vivo. Mechanistically, UXT binds to the promoters of the Notch signaling target genes and specifically interacts with the transactivation region domain of the Notch intracellular domain (NICD), impairing the interaction between NICD and the transcription factor RBP-Jκ endogenously. This prevents RBP-Jκ/CSL from activation and thus inhibits the consequent gene inductions. Furthermore, blockade of Notch signaling rescues the angiogenesis defect caused by UXT knockdown both in vitro and in vivo. Taken together, the data presented in this study characterize UXT as a novel repressor of Notch signaling, shedding new light on the molecular regulation of angiogenesis.
Highlights
The blood vessel network is composed of arteries, capillaries and veins
Using the whole-mount in situ hybridization (WISH) technique, we observed a ubiquitous expression of uxt mRNA as early as 6 hours post fertilization
The real-time quantitative PCR (RT-qPCR) results further substantiated the expression of uxt mRNA during zebrafish embryo development (Fig. 1C)
Summary
Vasculogenesis is a de novo assembly of the network, whereas angiogenesis is the coordinated growth of endothelial cells (ECs) from pre-existing vasculature (Risau, 1997; Risau and Flamme, 1995) Both processes are essential for tissue growth and organ function in development, physiology and disease (Phng and Gerhardt, 2009). Angiogenic sprouting in zebrafish is one of the best-characterized examples of angiogenesis both morphologically and mechanically (Childs et al, 2002; Lawson and Weinstein, 2002; Siekmann and Lawson, 2007) This model centers on the interplay between tip cell and stalk cells (Eilken and Adams, 2010; Gerhardt et al, 2003; Siekmann and Lawson, 2007). Displaying a gene expression profile distinct from that of the stalk cell, the tip cell is the spearhead
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