The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease

Trends Mol Med. 2010 Sep;16(9):417-25. doi: 10.1016/j.molmed.2010.07.003. Epub 2010 Aug 3.


Disorders of retinal vascular growth and function are responsible for vision loss in a variety of diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and retinal artery or vein occlusion. Over the past decade, a new signaling pathway that controls retinal vascular development has emerged from the study of inherited disorders - in both humans and mice - that are characterized by retinal hypovascularization. This pathway utilizes a glial-derived extracellular ligand, Norrin, that acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, Tspan12, on the surface of developing endothelial cells. The resulting signal controls a transcriptional program that regulates endothelial growth and maturation. It will be of great interest to determine whether modulating this pathway could represent a therapeutic approach to human retinal vascular disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Humans
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism*
  • Retinal Vein / growth & development*
  • Retinal Vein / metabolism
  • Signal Transduction*


  • Frizzled Receptors
  • Nerve Tissue Proteins