Norrin/Frizzled4 Signaling in Retinal Vascular Development and Blood Brain Barrier Plasticity
Open accessAbstract
Norrin/Frizzled4 (Fz4) signaling activates the canonical Wnt pathway to control retinal vascular development. Using genetically engineered mice, we show that precocious Norrin production leads to premature retinal vascular invasion and delayed Norrin production leads to characteristic defects in intraretinal vascular architecture. In genetic mosaics, wild-type endothelial cells (ECs) instruct neighboring Fz4(-/-) ECs to produce an architecturally normal mosaic vasculature, a cell nonautonomous effect. However, over the ensuing weeks, Fz4(-/-) ECs are selectively eliminated from the mosaic vasculature, implying the existence of a quality control program that targets defective ECs. In the adult retina and cerebellum, gain or loss of Norrin/Fz4 signaling results in a cell-autonomous gain or loss, respectively, of blood retina barrier and blood brain barrier function, indicating an ongoing requirement for Frizzled signaling in barrier maintenance and substantial plasticity in mature CNS vascular structure.
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Wnt signaling pathway including Wnt ligands, Norrins, Frizzled receptors, Lrp5/6 coreceptors, Gpr124 and Reck cofactors, and β-catenin are critical for both vascular development and barriergenesis.
“Wnt signaling pathway including Wnt ligands, Norrins, Frizzled receptors, Lrp5/6 coreceptors, Gpr124 and Reck cofactors, and 𝛃 -catenin are critical for both vascular development and barriergenesis (138, 332, 558, 636, 682, 689);”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [636]
The Discussion section on Frizzled signaling and vascular plasticity says canonical Wnt signaling is required for CNS endothelial cells to develop and maintain a blood–brain or blood–retina barrier, and identifies Norrin, Wnt ligands, and Frizzled receptors. The paper also links Lrp5 and β-catenin to vascular development, but the passages from our copy do not establish the claimed roles of Lrp6, Gpr124, or Reck. (LLM, conf=0.87)
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- Authors
- Wang, Y., Rattner, A., Zhou, Y., Williams, J., Smallwood, P. M., & Nathans, J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Nathans, Jeremy
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 151
- Issue
- 6
- Pages
- 1332-1344
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3535266
- OpenAlex
- W2017912617
- Cited by
- 406
- References
- 0
- Citations by year
- 2026: 38 · 2025: 37 · 2024: 36 · 2023: 26 · 2022: 39 · 2021: 32 · 2020: 30 · 2019: 29 · 2018: 24 · 2017: 30 · 2016: 20 · 2015: 29 · 2014: 29 · 2013: 7
- FWCI
- 10.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (R01EY018637)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Norrin, Wnt signaling, retinal vascular development, blood-retinal barrier, blood-brain barrier, endothelial cells, non-cell-autonomous signaling, vascular architecture, cerebellum, genetic mosaicism
- MeSH terms
- Animals, Blood-Brain Barrier, Blood-Retinal Barrier, Cell Movement, Eye Proteins, Humans, Mosaicism, Nerve Tissue Proteins, Neuronal Plasticity, Retina, Signal Transduction, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Proliferation, Frizzled Receptors, Mice
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