PUBLICATION
A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
- Authors
- Pradella, D., Deflorian, G., Pezzotta, A., Di Matteo, A., Belloni, E., Campolungo, D., Paradisi, A., Bugatti, M., Vermi, W., Campioni, M., Chiapparino, A., Scietti, L., Forneris, F., Giampietro, C., Volf, N., Rehman, M., Zacchigna, S., Paronetto, M.P., Pistocchi, A., Eichmann, A., Mehlen, P., Ghigna, C.
- ID
- ZDB-PUB-210824-1
- Date
- 2021
- Source
- Nature communications 12: 4872 (Journal)
- Registered Authors
- Deflorian, Gianluca
- Keywords
- none
- MeSH Terms
-
- Alternative Splicing
- Animals
- Apoptosis*
- Blood Vessels/growth & development*
- Colonic Neoplasms/blood supply
- Colonic Neoplasms/metabolism
- Endothelial Cells
- Humans
- Morphogenesis
- Neovascularization, Pathologic/metabolism
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Netrin Receptors/genetics
- Netrin Receptors/metabolism*
- Netrin-1/metabolism
- RNA Isoforms/genetics
- RNA Isoforms/metabolism*
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Survival Analysis
- Zebrafish
- PubMed
- 34381052 Full text @ Nat. Commun.
Citation
Pradella, D., Deflorian, G., Pezzotta, A., Di Matteo, A., Belloni, E., Campolungo, D., Paradisi, A., Bugatti, M., Vermi, W., Campioni, M., Chiapparino, A., Scietti, L., Forneris, F., Giampietro, C., Volf, N., Rehman, M., Zacchigna, S., Paronetto, M.P., Pistocchi, A., Eichmann, A., Mehlen, P., Ghigna, C. (2021) A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis. Nature communications. 12:4872.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping