Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-24998-6
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG-17395, IG-21966]
- AIRC fellowship for Italy
- Armenise-Harvard Foundation
- AIRC [MFAG 20075]
- Italian Ministry of Education, University and Research (MIUR)
- European Union [745934]
- INCA
- Ligue contre le Cancer
- ANR [17-CONV-0002, 10-LABX-0061]
- Marie Curie Actions (MSCA) [745934] Funding Source: Marie Curie Actions (MSCA)
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UNC5B is a Netrin-1 receptor expressed in endothelial cells that induces apoptosis in the absence of ligand. The authors identified an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.
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-Delta 8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Delta 8 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-Delta 8 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. UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.
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