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

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.

Axon guidance pathways modulate neurotoxicity of ALS-associated UBQLN2

“…Mammals harbor a single fra ortholog, DCC , and four closely related paralogs with homology to Unc-5 : UNC5A, UNC5B, UNC5C, and UNC5D . Among these, we focused on UNC5B , which is widely expressed in nervous tissue and has well-described roles in axon guidance and apoptosis regulation 41,42,52,53 . To assess contributions of DCC and UNC5B signaling to UBQLN2-associated toxicity, we transduced UBQLN2 4XALS iPSCs with lentiviral shRNA vectors targeting DCC or UNC5B and differentiated the cells into iMNs for neurite analysis.…”

“…UNC5 and DCC/Fra harbor extended cytoplasmic domains that regulate caspase activation and are themselves targets for caspase mediated cleavage 41,65 . Engagement by netrin ligand is thought to suppress the intrinsic apoptotic potential of the UNC5 death domain while g-secretase mediated cleavage of UNC5C has been linked to neuronal apoptosis in AD 41,52,62 . The contributions of UNC5B death signaling to toxicity phenotypes in UBQLN2 ALS iMNs and flies may be informed by separation of function mutants with reduced caspase recruitment potential.…”

Novel six-gene prognostic signature based on colon adenocarcinoma immune-related genes

“…GO enrichment analysis of the high-risk group indicated the main enrichment was in keratinocyte differentiation, skin development, collagen-containing extracellular matrix (ECM) external encapsulating structure development, and structural molecule activity. Pradella et al [ 27 ] revealed that Unc-5 netrin receptor B (UNC5B) is an axon guidance regulator whose expression is associated with tumor angiogenesis and poor prognosis. Mitra et al demonstrated that cell migration involves integrating ECM with the actin cytoskeleton through transmembrane receptors [ 28 ].…”

New kid on the block: Netrin‐1 as a novel player in the delicate molecular network of hepatic inflammation

“…These studies may furthermore shed light on the dependence of NTN1 binding to its receptors because an UNC5B splicing isoform skipping exon 8 has been demonstrated to regulate angiogenesis independently of NTN1 binding. [ 10 ] Integrative patient cohort studies including patients with CLD of different etiologies may uncover alterations in NTN1 signaling and downstream pathways. Because HCC is a very heterogenous disease developing over a long period of time, mouse models may not reflect the inflammatory mechanisms in humans; thus, a better understanding of NTN1 signaling in patients with HCC is required.…”