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PMID:15035989

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Citation

Xu, Q, Wang, Y, Dabdoub, A, Smallwood, PM, Williams, J, Woods, C, Kelley, MW, Jiang, L, Tasman, W, Zhang, K and Nathans, J (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 116:883-95

Abstract

Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.

Links

PubMed

Keywords

Animals; Binding Sites/genetics; Cells, Cultured; Cerebellum/blood supply; Cerebellum/cytology; Cerebellum/growth & development; Ear, Inner/blood supply; Ear, Inner/cytology; Ear, Inner/growth & development; Eye Proteins/genetics; Eye Proteins/metabolism; Female; Frizzled Receptors; Humans; LDL-Receptor Related Proteins; Ligands; Low Density Lipoprotein Receptor-Related Protein-5; Male; Mice; Mice, Knockout; Microscopy, Electron; Mutation/genetics; Neovascularization, Pathologic/genetics; Neovascularization, Pathologic/pathology; Neovascularization, Pathologic/physiopathology; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Organ Culture Techniques; Pedigree; Proteins/genetics; Proteins/metabolism; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Receptors, G-Protein-Coupled; Receptors, LDL/genetics; Receptors, LDL/metabolism; Retinal Diseases/genetics; Retinal Diseases/pathology; Retinal Diseases/physiopathology; Retinal Vessels/growth & development; Retinal Vessels/metabolism; Retinal Vessels/pathology; Signal Transduction/genetics; Wnt Proteins; Zebrafish Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LRP6

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP6

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP6

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDP

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61088

F

Seeded From UniProt

complete

MOUSE:NDP

enables

GO:0005125: cytokine activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NDP

located_in

GO:0062023: collagen-containing extracellular matrix

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NDP

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDP

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDP

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NDP

involved_in

GO:0035426: extracellular matrix-cell signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NDP

located_in

GO:0062023: collagen-containing extracellular matrix

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NDP

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NDP

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FZD4

enables

GO:0019955: cytokine binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P48744

F

Seeded From UniProt

complete

MOUSE:FZD4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0061304: retinal blood vessel morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0061301: cerebellum vasculature morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD4

involved_in

GO:0035426: extracellular matrix-cell signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD8

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FZD4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FZD4

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FZD4

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD3

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:LRP5

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LRP5

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP5

involved_in

GO:0035426: extracellular matrix-cell signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP5

involved_in

GO:0110135: Norrin signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP5

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRP5

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT1

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FZD8

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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