A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis.
Nat Commun
; 12(1): 4872, 2021 08 11.
Article
em En
| MEDLINE
| ID: mdl-34381052
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Vasos Sanguíneos
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Apoptose
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Isoformas de RNA
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Receptores de Netrina
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article