Xu Qiang, Wang Yanshu, Dabdoub Alain, Smallwood Philip M, Williams John, Woods Chad, Kelley Matthew W, Jiang Li, Tasman William, Zhang Kang, Nathans Jeremy
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2004 Mar 19;116(6):883-95. doi: 10.1016/s0092-8674(04)00216-8.
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.
诺里病和家族性渗出性玻璃体视网膜病变（FEVR）中均会出现视网膜血管化不完全的情况。诺里病基因的蛋白质产物诺里蛋白是一种生化功能未知的分泌蛋白。FEVR的一种类型是由卷曲蛋白4（Fz4）缺陷引起的，Fz4是一种假定的Wnt受体。我们在此表明，诺里蛋白和Fz4作为配体-受体对发挥作用，依据如下：（1）人类和小鼠中诺里蛋白和Fz4突变导致的血管表型相似；（2）诺里蛋白与Fz4结合的特异性和高亲和力；（3）诺里蛋白高效诱导经典Wnt途径的Fz4和低密度脂蛋白受体相关蛋白（Lrp）依赖性激活；（4）诺里蛋白和Fz4的疾病相关变体所显示的信号缺陷。这些数据定义了一个在眼和耳的血管发育中起核心作用的诺里蛋白-Fz4信号系统，并且表明与Wnts无关的配体可通过Fz受体发挥作用。
