Norrin, Frizzled-4, and Lrp5 Signaling in Endothelial Cells Controls a Genetic Program for Retinal Vascularization

摘要: Disorders of vascular structure and function play a central role in wide variety CNS diseases. Mutations the Frizzled-4 (Fz4) receptor, Lrp5 coreceptor, or Norrin ligand cause retinal hypovascularization, but mechanisms by which Norrin/Fz4/Lrp signaling controls development have not been defined. Using mouse genetic cell culture models, we show that loss Fz4 endothelial cells causes defective growth, leads to chronic reversible silencing neurons. Loss all disrupts blood brain barrier cerebellum, whereas excessive embryonic angiogenesis. Sox17, transcription factor is upregulated signaling, plays inducing angiogenic program controlled Norrin/Fz4/Lrp. These experiments establish cellular basis for hypovascularization diseases due insufficient Frizzled they suggest broader remodeling, maintenance, disease.