MiR-27b controls venous specification and tip cell fate

Biyashev, D., Veliceasa, D., Topczewski, J., Topczewska, J.M., Mizgirev, I., Vinokour, E., Reddi, A.L., Licht, J.D., Revskoy, S.Y., and Volpert, O.V.
Blood   119(11): 2679-2687 (Journal)
Registered Authors
Topczewski, Jacek
MeSH Terms
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Aorta/cytology
  • Aorta/metabolism
  • Arteries/embryology*
  • Arteries/metabolism
  • Biomarkers/metabolism
  • Blotting, Northern
  • Blotting, Western
  • Carcinoma, Lewis Lung/genetics
  • Carcinoma, Lewis Lung/metabolism
  • Carcinoma, Lewis Lung/pathology
  • Cell Differentiation
  • Cell Movement
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Endothelium, Vascular/cytology*
  • Endothelium, Vascular/metabolism
  • Gene Expression Profiling
  • Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins/genetics
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Membrane Proteins/antagonists & inhibitors
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs/physiology*
  • Neovascularization, Physiologic*
  • Oligonucleotide Array Sequence Analysis
  • Pseudopodia/metabolism
  • RNA, Messenger/genetics
  • RNA, Small Interfering/genetics
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/metabolism
22207734 Full text @ Blood

We discovered that miR-27b controls two critical vascular functions. It turns angiogenic switch on by promoting endothelial tip cell fate and sprouting. In addition, miR-27b promoted venous differentiation. We have identified its key targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). MiR-27b knock-down in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled expression of arterial and venous markers in human endothelium, including Ephrin B2, EphB4, Flt1 and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting, longer intersegmental vessels (ISV) and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the branched tip cells in the ISV. The blockade of both Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers in zebrafish embryo. Blocking either Spry2 or Dll4 rescued miR-27b knock-down phenotype in zebrafish and in mouse vascular explants pointing to essential roles of these targets downstream of miR-27b. Our study ascribes miR-27b critical role in control of the endothelial tip cell fate, branching and venous specification and identifies Spry2 and Dll4 as its essential targets.

Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes