Fzd4, short for Frizzled-4, is an important receptor for Wnt proteins. It activates several downstream signaling pathways, most notably the Wnt/β -catenin signaling pathway [1,5]. This gene plays a crucial role in various biological processes such as the formation of the blood-retina-barrier during development and its maintenance in adults, as well as in regulating stem cell specification and activity in different cell populations within organs like the lung [2,6]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been valuable in studying Fzd4.

In lung cancer, endothelial-specific deletion of FOXF1 decreased Wnt/β -catenin signaling in tumor-associated endothelial cells (TECs) through down-regulating Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs normalized tumor vessels and inhibited lung cancer progression, suggesting Fzd4 is crucial in maintaining tumor vessel stability [1]. In the context of familial exudative vitreoretinopathy (FEVR), whole-gene deletions of FZD4 were found in some patients, and the methylation level of FZD4 exon 1 was negatively linked with disease severity [3,4]. In addition, in an oxygen-induced retinopathy mouse model, Fzd4 haploinsufficiency led to delayed retinal revascularization [7].

In conclusion, Fzd4 is essential for the proper functioning of multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed its significance in diseases like lung cancer and FEVR. Understanding Fzd4's functions can provide new insights into the pathogenesis of these diseases and potentially lead to novel therapeutic strategies.

References:

1. Bian, Fenghua, Goda, Chinmayee, Wang, Guolun, Kalinichenko, Vladimir V, Kalin, Tanya V. 2024. FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4. In EMBO molecular medicine, 16, 1063-1090. doi:10.1038/s44321-024-00064-8. https://pubmed.ncbi.nlm.nih.gov/38589650/

2. Nabhan, Ahmad N, Webster, Joshua D, Adams, Jarret J, Arron, Joseph R, Dixit, Vishva M. 2023. Targeted alveolar regeneration with Frizzled-specific agonists. In Cell, 186, 2995-3012.e15. doi:10.1016/j.cell.2023.05.022. https://pubmed.ncbi.nlm.nih.gov/37321220/

3. Huang, Li, Lu, Jinglin, Zhang, Linyan, Cao, Liming, Ding, Xiaoyan. 2021. Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy. In Genes, 12, . doi:10.3390/genes12070980. https://pubmed.ncbi.nlm.nih.gov/34199009/

4. Liu, Miaomiao, Luo, Jia, Feng, Huazhang, Zhao, Peiquan, Fei, Ping. 2022. Decrease of FZD4 exon 1 methylation in probands from FZD4-associated FEVR family of phenotypic heterogeneity. In Frontiers in medicine, 9, 976520. doi:10.3389/fmed.2022.976520. https://pubmed.ncbi.nlm.nih.gov/36353221/

5. Xiang, Daimin, Gu, Mingye, Liu, Junyu, Fu, Jing, Wang, Hongyang. 2023. m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. In Cancer letters, 560, 216144. doi:10.1016/j.canlet.2023.216144. https://pubmed.ncbi.nlm.nih.gov/36958694/

6. Chidiac, Rony, Abedin, Md, Macleod, Graham, Junge, Harald J, Angers, Stephane. 2021. A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy. In EMBO molecular medicine, 13, e13977. doi:10.15252/emmm.202113977. https://pubmed.ncbi.nlm.nih.gov/34105895/

7. Ngo, Michael H, Borowska-Fielding, Joanna, Heathcote, Godfrey, McMaster, Christopher R, Robitaille, Johane M. 2016. Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy. In PloS one, 11, e0158320. doi:10.1371/journal.pone.0158320. https://pubmed.ncbi.nlm.nih.gov/27489958/