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

Davide Pradella (1, 2) , Gianluca Deflorian (3) , Alex Pezzotta (4) , Anna Di Matteo (1) , Elisa Belloni (1) , Daniele Campolungo (1, 5) , Andrea Paradisi (6, 7, 8) , Mattia Bugatti (9) , William Vermi (9, 10) , Matteo Campioni (2) , Antonella Chiapparino (2, 11) , Luigi Scietti (2) , Federico Forneris (2) , Costanza Giampietro (3, 12) , Nina Volf (13) , Michael Rehman (13, 14) , Serena Zacchigna (13, 15) , Maria Paola Paronetto (16, 17) , Anna Pistocchi (4) , Anne Eichmann (14, 18) , Patrick Mehlen (6, 7, 8) , Claudia Ghigna (1)

1 CNR - National Research Council of Italy | Consiglio Nazionale delle Ricerche
2 UNIPV - Università degli Studi di Pavia = University of Pavia
3 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
4 UNIMI - Università degli Studi di Milano = University of Milan
5 San Raffaele Scientific Institute
6 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
7 LabEx DEVweCAN - Développement Cancer et Thérapies Ciblées [Lyon]
8 Centre Léon Bérard [Lyon]
9 UniBs - Università degli Studi di Brescia = University of Brescia
10 Washington University School of Medicine in St. Louis
11 Universität Heidelberg [Heidelberg] = Heidelberg University
12 EMPA - Swiss Federal Laboratories for Materials Science and Technology [Dübendorf]
13 Trieste - International Centre for Genetic Engineering and Biotechnology (ICGEB)
14 YSM - Yale School of Medicine [New Haven, Connecticut]
15 Università degli studi di Trieste = University of Trieste
16 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
17 University of Rome “Foro Italico”
18 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire

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.

Domaines: Biologie cellulaire

Davide Pradella, Gianluca Deflorian, Alex Pezzotta, Anna Di Matteo, Elisa Belloni, et al.. A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis. Nature Communications, 2021, 12 (1), pp.4872. ⟨10.1038/s41467-021-24998-6⟩. ⟨hal-03357307⟩