BACKGROUND: The interplay between Notch and Vegf signaling regulates angiogenesis in the embryo. Notch signaling limits the responsiveness of endothelial cells to Vegf to control sprouting. Despite the importance of this regulatory relationship, much remains to be understood about extrinsic factors that modulate the pathway. RESULTS: During a forward genetic screen for novel regulators of lymphangiogenesis, we isolated a mutant with reduced lymphatic vessel development. This mutant also exhibited hyperbranching arteries, reminiscent of Notch pathway mutants. Positional cloning identified a missense mutation in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) gene. Cad is essential for UDP biosynthesis, which is necessary for protein glycosylation and de novo biosynthesis of pyrimidine-based nucleotides. Using a transgenic reporter of Notch activity, we demonstrate that Notch signaling is significantly reduced in cad(hu10125) mutants. In this context, genetic epistasis showed that increased endothelial cell responsiveness to Vegfc/Vegfr3 signaling drives excessive artery branching. CONCLUSIONS: These findings suggest important posttranslational modifications requiring Cad as an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis.
BACKGROUND: The interplay between Notch and Vegf signaling regulates angiogenesis in the embryo. Notch signaling limits the responsiveness of endothelial cells to Vegf to control sprouting. Despite the importance of this regulatory relationship, much remains to be understood about extrinsic factors that modulate the pathway. RESULTS: During a forward genetic screen for novel regulators of lymphangiogenesis, we isolated a mutant with reduced lymphatic vessel development. This mutant also exhibited hyperbranching arteries, reminiscent of Notch pathway mutants. Positional cloning identified a missense mutation in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) gene. Cad is essential for UDP biosynthesis, which is necessary for protein glycosylation and de novo biosynthesis of pyrimidine-based nucleotides. Using a transgenic reporter of Notch activity, we demonstrate that Notch signaling is significantly reduced in cad(hu10125) mutants. In this context, genetic epistasis showed that increased endothelial cell responsiveness to Vegfc/Vegfr3 signaling drives excessive artery branching. CONCLUSIONS: These findings suggest important posttranslational modifications requiring Cad as an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis.
Authors: Ivy Kim-Ni Chiang; Martin Fritzsche; Cathy Pichol-Thievend; Alice Neal; Kelly Holmes; Anne Lagendijk; Jeroen Overman; Donatella D'Angelo; Alice Omini; Dorien Hermkens; Emmanuelle Lesieur; Ke Liu; Indrika Ratnayaka; Monica Corada; George Bou-Gharios; Jason Carroll; Elisabetta Dejana; Stefan Schulte-Merker; Benjamin Hogan; Monica Beltrame; Sarah De Val; Mathias Francois Journal: Development Date: 2017-06-15 Impact factor: 6.868
Authors: Xianyu Hu; Suwen Bai; Lingyi Li; Pengfei Tian; Sun Wang; Ning Zhang; Bing Shen; Juan Du; Shengxiu Liu Journal: Exp Biol Med (Maywood) Date: 2021-01-20
Authors: Katarzyna Koltowska; Scott Paterson; Neil I Bower; Gregory J Baillie; Anne K Lagendijk; Jonathan W Astin; Huijun Chen; Mathias Francois; Philip S Crosier; Ryan J Taft; Cas Simons; Kelly A Smith; Benjamin M Hogan Journal: Genes Dev Date: 2015-08-01 Impact factor: 11.361