Abstract
Vascular morphogenesis requires a delicate gradient of Notch signaling controlled, in part, by the distribution of ligands (Dll4 and Jagged1). How Jagged1 (JAG1) expression is compartmentalized in the vascular plexus remains unclear. Here, we show that Jag1 mRNA is a direct target of zinc-finger protein 36 (ZFP36), an RNA-binding protein involved in mRNA decay that we find robustly induced by vascular endothelial growth factor (VEGF). Endothelial cells lacking ZFP36 display high levels of JAG1 and increase angiogenic sprouting in vitro. Furthermore, mice lacking Zfp36 in endothelial cells display mispatterned and increased levels of JAG1 in the developing retinal vascular plexus. Abnormal levels of JAG1 at the sprouting front alters NOTCH1 signaling, increasing the number of tip cells, a phenotype that is rescued by imposing haploinsufficiency of Jag1. Our findings reveal an important feedforward loop whereby VEGF stimulates ZFP36, consequently suppressing Jag1 to enable adequate levels of Notch signaling during sprouting angiogenesis.
| Original language | English (US) |
|---|---|
| Article number | 113627 |
| Journal | Cell reports |
| Volume | 43 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 23 2024 |
Funding
We thank the Broad Stem Cell Research Center (BSCRC) and Jonsson Comprehensive Cancer Center (JCCC) at UCLA for sequencing libraries, the Feinberg School of Medicine, and the Robert H. Lurie Comprehensive Cancer Center (RHLCCC) and associated core facilities at Northwestern University (supported by Cancer Center Support grant NCI CA060553 ): the Mouse Histology and Phenotyping Core, RHLCCC Flow Cytometry Facility, and Center for Advanced Microscopy. A special thanks goes to Michelle Steel and Snezana Mirkov for assistance with husbandry and animal experiments. This work was supported by the NIH ( R35HL140014 to M.L.I.-A.) and Ruth L. Kirschstein National Research Service Awards ( GM007185 and T32HL069766 ) and a Whitcome Fellowship (UCLA) (to H.L.S.). We thank the Broad Stem Cell Research Center (BSCRC) and Jonsson Comprehensive Cancer Center (JCCC) at UCLA for sequencing libraries, the Feinberg School of Medicine, and the Robert H. Lurie Comprehensive Cancer Center (RHLCCC) and associated core facilities at Northwestern University (supported by Cancer Center Support grant NCI CA060553): the Mouse Histology and Phenotyping Core, RHLCCC Flow Cytometry Facility, and Center for Advanced Microscopy. A special thanks goes to Michelle Steel and Snezana Mirkov for assistance with husbandry and animal experiments. This work was supported by the NIH (R35HL140014 to M.L.I.-A.) and Ruth L. Kirschstein National Research Service Awards (GM007185 and T32HL069766) and a Whitcome Fellowship (UCLA) (to H.L.S.). Conceptualization, H.L.S. and M.L.I.-A.; methodology, H.L.S. A.C.C. D.P. and V.S.; validation, H.L.S. and A.C.C.; formal analysis, H.L.S. A.C.C. K.E.K.-U. F.M. C.S. and V.S.; investigation, H.L.S. and A.C.C.; resources, A.C.C. K.E.K.-U. F.M. V.S. H.R.C. M.T. and T.A.V.; data curation, K.E.K.-U.; writing – original draft, H.L.S. and M.L.I.-A.; writing – review & editing, H.L.S. A.C.C. H.R.C. T.A.V. and M.L.I.-A.; funding acquisition, H.L.S. and M.L.I.-A.; aupervision, H.R.C. T.A.V. and M.L.I.-A. The authors declare no competing interests.
Keywords
- CP: Cell biology
- CP: Molecular biology
- RNA-decay
- VEGF
- angiogenesis
- notch
- tristetraproline
- vascular morphogenesis
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
