Other
14 Authors
- Yuan JJ,
- Kuo CJ,
- Mu Q,
- Santos AJM,
- Li L,
- Miao Y,
- Tomaske M,
- Guzman VK,
- Ha A,
- van Unen V,
- Deng L,
- Alwahabi S,
- Garcia KC,
- Lo YH
| First Author | Mu Q | Year | 2025 |
| Journal | Dev Cell | Volume | 60 |
| Issue | 3 | Pages | 342-351.e5 |
| PubMed ID | 39579768 | Mgi Jnum | J:360798 |
| Mgi Id | MGI:7790372 | Doi | 10.1016/j.devcel.2024.10.022 |
| Citation | Mu Q, et al. (2024) FZD5 controls intestinal crypt homeostasis and colonic Wnt surrogate agonist response. Dev Cell |
| abstractText | The rapidly regenerating intestinal epithelium requires crypt intestinal stem cells (ISCs). Wnt/beta-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 beta-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. |
