FZD4 (frizzled class receptor 4) functions as a critical G-protein coupled receptor for Wnt proteins and norrin, primarily activating the canonical β-catenin signaling pathway 1. The protein plays essential roles in vascular development, particularly in retinal and cochlear microvasculature, where it responds to both Wnt proteins and norrin (NDP) to promote β-catenin accumulation and LEF/TCF-mediated transcriptional programs 2. FZD4 cooperates with co-receptors LRP5/LRP6 to activate downstream signaling cascades that regulate vascular barrier function and endothelial cell homeostasis 3. Mutations in FZD4 are strongly associated with familial exudative vitreoretinopathy (FEVR), a hereditary retinal vascular disorder characterized by peripheral retinal avascularity and potential vision loss 45. The protein's C-terminal domain (amino acids 495-537) containing PDZ binding motifs appears particularly critical for normal function, as FEVR-associated missense mutations frequently affect this region 6. Beyond ocular disease, FZD4 demonstrates tumor suppressor properties in cutaneous squamous cell carcinoma and promotes vessel normalization in lung cancer through Wnt/β-catenin signaling 78. FZD4 represents a key therapeutic target for retinal vascular diseases and cancer treatment strategies.