Norrin, Frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization.

摘要

Disorders of vascular development or function play a central role in a wide variety of CNS diseases. Mutations in the Frizzled4 (Fz4) receptor, Lrp5 co-receptor, or Norrin ligand cause retinal hypovascularization with associated vision loss, but the pathophysiology of these disorders and the normal cellular and molecular roles of Norrin/Fz4/Lrp signaling have not been defined. Using mouse genetic and cell culture models, we show that these disorders are caused by defective endothelial cell growth and patterning due to the loss of Fz4 signaling in both endothelial and mural cells, which in turn leads to neuronal dysfunction through chronic but reversible silencing of inner retinal neurons. Furthermore, loss of Fz4 in all endothelial cells disrupts the blood brain barrier in the cerebellum, resulting in progressive neuronal degeneration, while excessive Fz4 signaling disrupts embryonic angiogenesis. Finally, we present evidence that Sox17, a transcription factor that is strongly up-regulated by Norrin/Fz4/Lrp signaling, plays a central role in inducing the angiogenic program controlled by Norrin/Fz4/Lrp. These experiments establish Frizzled signaling as a critical regulator of vascular development in the brain and retina, and they suggest a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.