{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Frizzled‐4 (FZD4) is a member of the Wnt receptor family that plays a pivotal role in mediating signaling pathways essential for vascular development and tissue homeostasis. A series of studies have firmly established that FZD4 functions as the receptor for the secreted ligand Norrin, thereby activating canonical Wnt/β‐catenin and associated non‐canonical pathways critical for retinal and inner ear angiogenesis and the maintenance of blood–retina and blood–brain barrier properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Mutations in FZD4 disrupt ligand binding, receptor multimerization, and subsequent downstream signaling (including activation of effectors such as CAMKII and PKC), leading to conditions such as familial exudative vitreoretinopathy (FEVR)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, accessory molecules such as TSPAN12 have been shown to cooperate with FZD4 to promote efficient receptor multimerization and robust Norrin‐induced signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Regulation of FZD4 activation also involves receptor internalization; for example, its endocytosis is modulated by Dishevelled recruitment and β‐arrestin interaction, serving as a critical checkpoint for signaling output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its established role in neurovascular development, aberrant FZD4 expression has been implicated in pathological contexts. In prostate cancer, oncogenic factors such as ERG modulate FZD4 levels, thereby contributing to epithelial–mesenchymal transition and loss of cell adhesion, which promote tumor invasiveness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, in ovarian physiology, FZD4 is expressed in granulosa cells, where its proper function is necessary for corpus luteum formation and endocrine regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore FZD4 as a central mediator of Wnt signaling with diverse roles ranging from the regulation of retinal vascularization and barrier maintenance to contributions in oncogenic processes and reproductive function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}, {"type": "fg_fs", "start_ref": "6", "end_ref": "9"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qiang Xu, Yanshu Wang, Alain Dabdoub, et al. 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