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

Xin Ye1, Yanshu Wang, Hugh Cahill

  • 1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Cell
|October 20, 2009
PubMed

Insights

Norrin/Frizzled-4 (Fz4) signaling is crucial for vascular development. Loss of Fz4 in endothelial cells impairs blood vessel growth, leading to retinal neuron dysfunction and potential central nervous system vascular issues.

Area of Science:

  • Vascular biology
  • Neuroscience
  • Developmental biology

Background:

  • Vascular structure and function are critical in central nervous system (CNS) diseases.
  • Mutations in Frizzled-4 (Fz4), Lrp5, or Norrin cause retinal hypovascularization, but the underlying mechanisms are unclear.

Purpose of the Study:

  • To define the mechanisms by which Norrin/Fz4/Lrp signaling controls vascular development.
  • To investigate the cellular basis of retinal hypovascularization diseases.

Main Methods:

  • Utilized mouse genetic models and cell culture.
  • Analyzed the role of Frizzled-4 (Fz4) signaling in endothelial cells.
  • Investigated the function of the transcription factor Sox17.

Main Results:

  • Loss of Fz4 signaling in endothelial cells resulted in defective vascular growth and reversible retinal neuron silencing.
  • Disruption of Fz4 in endothelial cells compromised the blood-brain barrier in the cerebellum.
  • Excessive Fz4 signaling disrupted embryonic angiogenesis.
  • Sox17, upregulated by Norrin/Fz4/Lrp signaling, is central to the angiogenic program.

Conclusions:

  • Established a cellular basis for retinal hypovascularization diseases linked to insufficient Frizzled signaling.
  • Suggests a broader role for Frizzled signaling in vascular growth, remodeling, maintenance, and disease.

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