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Endothelial Jagged1 levels and distribution are post-transcriptionally controlled by ZFP36 decay proteins

ABSTRACT: Vascular morphogenesis requires a delicate gradient of Notch signaling that is controlled, at least in part, by the distribution of ligands (Dll4 and Jagged1). How jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here we showed that Jag1 mRNA is a direct target of zinc finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we found robustly induced by VEGF. Endothelial cells lacking ZFP36 displayed high levels of JAG1 and increased angiogenic sprouting in vitro. Similarly, mice lackingZfp36in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front altered NOTCH1 signaling, increasing the number of tip cells; a phenotype that was rescued by imposing haploinsufficiency ofJag1. Our findings reveal an important feedforward loop, whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235462 | GEO | 2023/12/04

REPOSITORIES: GEO

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Effect of VEGF on expressions of C2H2 zinc finger proteins in human umbilical vein endothelial cells.

Project description:Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signalling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signalling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signalling factor CBF1, and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF-/- mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signalling. Human umbilical vein endothelial cells were stimulated with recombinant human VEGF165 for 0, 1, 2, 6, 12, 24 and 48 hours.

2012-03-25 | E-GEOD-35171 | biostudies-arrayexpress

Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade

Project description:Coronaries are essential for myocardial growth and heart function. Notch is crucial for mouse embryonic angiogenesis, but its role in coronary development remains uncertain. We show Jag1, Dll4 and activated Notch1 receptor expression in sinus venosus (SV) endocardium. Endocardial Jag1 removal blocks SV capillary sprouting, while Dll4 inactivation stimulates excessive capillary growth, suggesting that ligand antagonism regulates coronary primary plexus formation. Later endothelial ligand removal, or forced expression of Dll4 or the glycosyltransferase MFng, blocks coronary plexus remodeling, arterial differentiation, and perivascular cell maturation. Endocardial deletion of Efnb2 phenocopies the coronary arterial defects of Notch mutants. Angiogenic rescue experiments in ventricular explants, or in primary human endothelial cells, indicate that EphrinB2 is a critical effector of antagonistic Dll4 and Jag1 functions in arterial morphogenesis. Thus, coronary arterial precursors are specified in the SV prior to primary coronary plexus formation and subsequent arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade.

2019-12-03 | GSE110614 | GEO

Loss of Jagged1 in mature endothelial cells causes vascular dysfunction with alterations in smooth muscle phenotypes

Project description:Notch signaling is an evolutionarily conserved pathway that functions via direct cell-cell contact. The Notch ligand Jagged1 (Jag1) has been extensively studied in vascular development, particularly for its role in smooth muscle cell maturation. Endothelial cell-expressed Jag1 is essential for blood vessel formation by signaling to nascent vascular smooth muscle cells and promoting their differentiation. Given the established importance of Jag1 in endothelial cell/smooth muscle crosstalk during development, we sought to determine the extent of this communication in the adult vasculature for blood vessel function and homeostasis.

2022-08-01 | GSE209736 | GEO

Effect of VEGF on expressions of C2H2 zinc finger proteins in human umbilical vein endothelial cells.

2012-03-25 | GSE35171 | GEO

β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects.

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Pro-angiogenic transcriptome of zebrafish endothelial cells

Project description:To identify previously unknown determinants of endothelial cell sprouting, we defined and exploited a pharmacological strategy for the manipulation of angiogenic cell behavior in vivo. Whereas high vascular endothelial growth factor receptor (Vegfr) signaling is known to promote tip cell (TC) specification, activation of the Notch receptor via its ligand Delta-like 4 (Dll4) represses the TC phenotype to promote stalk cell (SC) fate. Conversely, suppression of Notch activity upon antagonistic interaction with its ligand Jagged1 pro- motes TC formation. Hence, specification of TCs involves tight spatiotemporal control of Vegfr/Notch signaling. Consequently, we hypothesized that the pharmacological manipulation of Vegfr/Notch signaling selectively during zebrafish intersegmental vessel (ISV) angiogenesis would enable the precise control of angiogenic EC behavior and sprouting- associated gene expression in vivo. For more information, see Herbert et al., 2012, PMID 22921365.

2019-05-09 | GSE130889 | GEO

HEK NICD AP-MS - Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs)

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2019-04-11 | PXD013192 | Pride

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2018-08-29 | GSE39180 | GEO

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Project description:To obtain a Notch-depleted base cell line into which we could integrate specific ligands or receptors for quantitative analysis of Notch signaling interactions, we conducted 2 rounds of transfection with RNPs (ribonucleoproteins) consisting of gRNAs targeting Notch2 and Jagged1 complexed with Cas9 protein. After antibiotic selection and screening of monoclonal colonies, we obtained the C2C12-Nkd clone, which showed loss of Notch2 protein and Jag1 transcript.

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BMP/Taz-Hippo signaling modulates VEGF-mediated angiogenesis

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