A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis.
Alternative Splicing
Animals
Apoptosis
Blood Vessels
/ growth & development
Colonic Neoplasms
/ blood supply
Endothelial Cells
Humans
Morphogenesis
Neovascularization, Pathologic
/ metabolism
Nerve Tissue Proteins
/ genetics
Netrin Receptors
/ genetics
Netrin-1
/ metabolism
Neuro-Oncological Ventral Antigen
RNA Isoforms
/ genetics
RNA-Binding Proteins
/ genetics
Survival Analysis
Zebrafish
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 08 2021
11 08 2021
Historique:
received:
03
08
2020
accepted:
16
07
2021
entrez:
12
8
2021
pubmed:
13
8
2021
medline:
24
8
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34381052
doi: 10.1038/s41467-021-24998-6
pii: 10.1038/s41467-021-24998-6
pmc: PMC8358048
doi:
Substances chimiques
NOVA2 protein, human
0
Nerve Tissue Proteins
0
Netrin Receptors
0
Neuro-Oncological Ventral Antigen
0
RNA Isoforms
0
RNA-Binding Proteins
0
Netrin-1
158651-98-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4872Informations de copyright
© 2021. The Author(s).
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