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.

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis / D. Pradella, G. Deflorian, A. Pezzotta, A. Di Matteo, E. Belloni, D. Campolungo, A. Paradisi, M. Bugatti, W. Vermi, M. Campioni, A. Chiapparino, L. Scietti, F. Forneris, C. Giampietro, N. Volf, M. Rehman, S. Zacchigna, M.P. Paronetto, A. Pistocchi, A. Eichmann, P. Mehlen, C. Ghigna. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 12:1(2021 Aug 11), pp. 4872.1-4872.17. [10.1038/s41467-021-24998-6]

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

A. Pezzotta;C. Giampietro;A. Pistocchi;
2021-08-11

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.
Alternative Splicing; Animals; Blood Vessels; Colonic Neoplasms; Endothelial Cells; Humans; Morphogenesis; Neovascularization, Pathologic; Nerve Tissue Proteins; Netrin Receptors; Netrin-1; RNA Isoforms; RNA-Binding Proteins; Survival Analysis; Zebrafish; Apoptosis
Settore BIO/13 - Biologia Applicata
Settore MED/04 - Patologia Generale
Settore BIO/11 - Biologia Molecolare
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/863684
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