A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

22The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.openopenPradella D.; Deflorian G.; Pezzotta A.; Di Matteo A.; Belloni E.; Campolungo D.; Paradisi A.; Bugatti M.; Vermi W.; Campioni M.; Chiapparino A.; Scietti L.; Forneris F.; Giampietro C.; Volf N.; Rehman M.; Zacchigna S.; Paronetto M.P.; Pistocchi A.; Eichmann A.; Mehlen P.; Ghigna C.Pradella, D.; Deflorian, G.; Pezzotta, A.; Di Matteo, A.; Belloni, E.; Campolungo, D.; Paradisi, A.; Bugatti, M.; Vermi, W.; Campioni, M.; Chiapparino, A.; Scietti, L.; Forneris, F.; Giampietro, C.; Volf, N.; Rehman, M.; Zacchigna, S.; Paronetto, M. P.; Pistocchi, A.; Eichmann, A.; Mehlen, P.; Ghigna, C