Journal Article

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

Paradisi, Andrea, Pistocchi, Anna, Deflorian, Gianluca, Belloni, Elisa, Bugatti, Mattia, Pezzotta, Alex, Chiapparino, Antonella, Paronetto, Maria Paola, Mehlen, Patrick, Zacchigna, Serena, Forneris, Federico, Campolungo, Daniele, Eichmann, Anne, Di Matteo, Anna, Campioni, Matteo, Scietti, Luigi, Pradella, Davide, Vermi, William, Giampietro, Costanza, Rehman, Michael, Volf, Nina, Ghigna, Claudia

2021

Overview

The 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. UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/109 / 13/2 / 13/89 / 14 / 14/19 / 14/35 / 14/63 / 38 / 38/109 / 38/77 / 38/88 / 38/90 / 631/136/16 / 631/337/1645/1946 / 631/67/2328 / 631/80/82/23 / 64 / 64/116 / 82/103 / 82/29 / 82/83 / Alternative Splicing / Angiogenesis / Animals / Apoptosis / Axon guidance / Blood Vessels / Cellular Biology / Circuits / Colon / Colon cancer / Colonic Neoplasms / Colorectal cancer / Endothelial Cells / Exon skipping / Humanities and Social Sciences / Humans / Life Sciences / Ligands / Morphogenesis / multidisciplinary / Neovascularization, Pathologic / Nerve Tissue Proteins / Netrin Receptors / Netrin-1 / Post-transcription / Receptors / RNA Isoforms / RNA-Binding Proteins / Science / Science (multidisciplinary) / Splicing / Splicing factors / Survival Analysis / Tumors / Zebrafish