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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number4872
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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