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

Author

Listed:
  • Davide Pradella

    (Consiglio Nazionale delle Ricerche
    University of Pavia)

  • Gianluca Deflorian

    (IFOM, The FIRC Institute of Molecular Oncology
    Cogentech, Società Benefit)

  • 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
    IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology)

  • Andrea Paradisi

    (Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard)

  • Mattia Bugatti

    (University of Brescia)

  • William Vermi

    (University of Brescia
    Washington University School of Medicine)

  • Matteo Campioni

    (University of Pavia)

  • Antonella Chiapparino

    (University of Pavia
    Heidelberg University Biochemistry Center (BZH), INF 328)

  • Luigi Scietti

    (University of Pavia)

  • Federico Forneris

    (University of Pavia)

  • Costanza Giampietro

    (IFOM, The FIRC Institute of Molecular Oncology
    Experimental Continuum Mechanics EMPA)

  • 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
    Section of Nephrology)

  • Serena Zacchigna

    (International Centre for Genetic Engineering and Biotechnology (ICGEB), AREA Science Park, Padriciano 99
    University of Trieste)

  • Maria Paola Paronetto

    (IRCCS Santa Lucia Foundation
    University of Rome “Foro Italico”)

  • Anna Pistocchi

    (University of Milan—LITA)

  • Anne Eichmann

    (Cardiovascular Research Center, Yale University School of Medicine, Department of Internal Medecine Cardiology
    INSERM U970, Paris Center for Cardiovascular Research (PARCC)
    Yale University School of Medicine)

  • Patrick Mehlen

    (Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard)

  • Claudia Ghigna

    (Consiglio Nazionale delle Ricerche)

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.

Suggested Citation

  • Davide Pradella & Gianluca Deflorian & Alex Pezzotta & Anna Di Matteo & Elisa Belloni & Daniele Campolungo & Andrea Paradisi & Mattia Bugatti & William Vermi & Matteo Campioni & Antonella Chiapparino , 2021. "A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24998-6
    DOI: 10.1038/s41467-021-24998-6
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