TY - JOUR
T1 - Vascular development in the retina and inner ear
T2 - Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair
AU - Xu, Qiang
AU - Wang, Yanshu
AU - Dabdoub, Alain
AU - Smallwood, Philip M.
AU - Williams, John
AU - Woods, Chad
AU - Kelley, Matthew W.
AU - Jiang, Li
AU - Tasman, William
AU - Zhang, Kang
AU - Nathans, Jeremy
N1 - Funding Information:
The authors thank Marcus Fruttiger and Randy Reed for advice; Carol Cooke for assistance with electron microscopy; Hugh Cahill and David Ryugo for performing ABR measurements; Dan Leahy for assistance with structural modeling; Fred Hess for Lrp plasmids; John Flanagan and Amir Rattner for AP plasmids; Randall Moon for the STF reporter plasmid; Jen-Chih Hsieh for the mFz4 stable cell line; Tudor Badea, David Ginty, Dan Leahy, Amir Rattner, Thomas Rotolo, David Valle, and Don Zack for helpful comments on the manuscript; and Terry Stromski for secretarial assistance. Supported by the Howard Hughes Medical Institute (Q.X., Y.W., P.M.S., J.W., J.N.), the National Institutes of Health (A.D., C.W., M.W.K.), the National Eye Institute (NIH), the Ruth and Milton Steinbach Fund, and the Ronald McDonald House Charities Fund (L.J., K.Z.).
PY - 2004/3/19
Y1 - 2004/3/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=12144289950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12144289950&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(04)00216-8
DO - 10.1016/S0092-8674(04)00216-8
M3 - Article
C2 - 15035989
AN - SCOPUS:12144289950
SN - 0092-8674
VL - 116
SP - 883
EP - 895
JO - Cell
JF - Cell
IS - 6
ER -