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 Eichmann, Patrick Mehlen and Claudia Ghigna ()
Additional contact information
Davide Pradella: Consiglio Nazionale delle Ricerche
Gianluca Deflorian: IFOM, The FIRC Institute of Molecular Oncology
Alex Pezzotta: University of Milan—LITA
Anna Di Matteo: Consiglio Nazionale delle Ricerche
Elisa Belloni: Consiglio Nazionale delle Ricerche
Daniele Campolungo: Consiglio Nazionale delle Ricerche
Andrea Paradisi: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Mattia Bugatti: University of Brescia
William Vermi: University of Brescia
Matteo Campioni: University of Pavia
Antonella Chiapparino: University of Pavia
Luigi Scietti: University of Pavia
Federico Forneris: University of Pavia
Costanza Giampietro: IFOM, The FIRC Institute of Molecular Oncology
Nina Volf: International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, Padriciano 99
Michael Rehman: International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, Padriciano 99
Serena Zacchigna: International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, Padriciano 99
Maria Paola Paronetto: IRCCS Santa Lucia Foundation
Anna Pistocchi: University of Milan—LITA
Anne Eichmann: Cardiovascular Research Center, Yale University School of Medicine, Department of Internal Medecine Cardiology
Patrick Mehlen: Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard
Claudia Ghigna: Consiglio Nazionale delle Ricerche

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24998-6

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DOI: 10.1038/s41467-021-24998-6

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