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

Hannah L. Sunshine, Andrew C. Cicchetto, Karolina Elżbieta Kaczor-Urbanowicz, Feiyang Ma, Danielle Pi, Chloe Symons, Martin Turner, Vipul Shukla, Heather R. Christofk, Thomas A. Vallim, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Article number113627
JournalCell reports
Volume43
Issue number1
DOIs
StatePublished - Jan 23 2024

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

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