The rapidly regenerating intestinal epithelium requires crypt intestinal stem cells (ISCs). Wnt/β-catenin signaling maintains crypt homeostasis and Lgr5+ ISCs, and WNT ligands bind Frizzled receptors (FZD1–10). Identifying specific FZD(s) essential for intestinal homeostasis has been elusive; however, bioengineered antagonists blocking Wnt binding to FZD5 and FZD8 deplete the gut epithelium in vivo, highlighting potential roles. Here, an epithelial-specific Fzd5 knockout (KO) elicited lethal pan-intestinal crypt and villus loss, whereas an Lgr5+ ISC-specific Fzd5 KO depleted Lgr5+ ISCs via premature differentiation and repressed Wnt target genes. Fzd5-null phenotypes were rescued by constitutive β-catenin activation in vivo and in both mouse and human enteroids. KO of Fzd5, not Fzd8, in enteroids ablated responsiveness to dual-specificity FZD5/FZD8-selective Wnt surrogate agonists, which ameliorated DSS-induced colitis in wild-type and Fzd8 KO mice. Overall, FZD5 is a dominant and essential regulator of crypt homeostasis, Lgr5+ ISCs, and intestinal response to Wnt surrogate agonists, with implications for therapeutic mucosal repair.

中文翻译：

---

FZD5 控制肠隐窝稳态和结肠 Wnt 替代激动剂反应


快速再生的肠上皮需要隐窝肠干细胞 （ISC）。Wnt/β-catenin 信号转导维持隐窝稳态和 Lgr5+ ISC，WNT 配体结合卷曲受体 （FZD1-10）。确定对肠道稳态至关重要的特定 FZD 一直难以捉摸;然而，阻断 Wnt 与 FZD5 和 FZD8 结合的生物工程拮抗剂会在体内耗尽肠道上皮 ，突出了潜在作用。在这里，上皮特异性 Fzd5 敲除 （KO） 引发致命的泛肠隐窝和绒毛丢失，而 Lgr5 + ISC 特异性 Fzd5 KO 通过过早分化和抑制 Wnt 靶基因耗尽 Lgr5 + ISC。Fzd5 缺失表型在体内以及小鼠和人肠样体中通过组成型 β-catenin 激活 得到挽救。在类肠类药物中 Fzd5 而不是 Fzd8 的 KO 消融了对双特异性 FZD5/FZD8 选择性 Wnt 替代激动剂的反应性，从而改善了野生型和 Fzd8 KO 小鼠中 DSS 诱导的结肠炎。总体而言，FZD5 是隐窝稳态、Lgr5+ ISC 和肠道对 Wnt 替代激动剂的反应的主要和重要调节因子，对治疗性粘膜修复有影响。