FAT4, also known as FAT Atypical Cadherin 4, is a member of the cadherin-associated protein family. It has crucial functions in multiple biological processes, such as cell-cell adhesion, and is involved in pathways like Wnt/β-catenin, Hippo, and MAPK [1,5,7,8]. FAT4 is important for normal development and tumor suppression [1,4,5,6,7,8]. Genetic models, including KO/CKO mouse models, have been used to study its functions.

In mouse models, deletion of Fat4 leads to abnormal kidney development with abnormal ureteric budding and excessive RET signaling, indicating its role in fine-tuning RET signaling during kidney development [3]. In osteoblast differentiation, Fat4 and Dchs1 mutants mimic human craniofacial phenotypes, and Dchs1-Fat4 signaling is essential for osteoblast differentiation. Loss of this signaling increases osteoprogenitor proliferation and delays osteoblast differentiation [2]. In HCC, knockout of FAT4 in normal human hepatic cells promotes tumor initiation through the switching of canonical to noncanonical WNT signaling pathways [5]. In endometrial cancer, stable FAT4 knockdown promotes cell lines proliferation and invasion, while overexpression inhibits the parental cell phenotype, with FAT4-USP51 complex regulating the process via the Hippo pathway [7].

In conclusion, FAT4 is essential for normal development and plays a significant role in tumor-related processes. KO/CKO mouse models have been instrumental in revealing its functions in kidney development, osteoblast differentiation, and cancer-related conditions like hepatocarcinogenesis and endometrial cancer, providing insights into disease mechanisms and potential therapeutic targets.