Fgf9, or Fibroblast growth factor 9, is a cytokine involved in multiple biological processes such as cell proliferation, differentiation, and tissue repair. It exerts its functions through various signaling pathways including ERK1/2-GSK-3β, PI3K/AKT/Hippo, MAPK/ERK, and Wnt/β-catenin/TCF7L2 [1,2,3]. Fgf9 is crucial for maintaining normal physiological functions and its dysregulation is associated with many diseases. Genetic models, especially KO/CKO mouse models, have been instrumental in uncovering its functions.

In NASH-driven HCC, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden in mice, while hepatocyte-specific FGF9 transgenic mice showed increased hepatic ECM and tumor burden, indicating FGF9 promotes NASH-driven HCC through the ECM pathway [1]. In osteoporosis, Fgf9 loss-of-function mutation (S99N) inhibited bone marrow adipose tissue formation and alleviated ovariectomy-induced bone loss, revealing its role in regulating bone-fat balance [2]. Fgf9 -/- mice exhibited 100% penetrance of cleft palate, showing its importance in palatogenesis [3]. The Fgf9S99N mutation in mice led to reduced ameloblasts and impaired enamel formation, highlighting its role in dental epithelial stem cell survival and enamel formation [4].

In conclusion, Fgf9 is essential for various biological processes including tumorigenesis, bone-fat balance, palatogenesis, and tooth development. The use of KO/CKO mouse models has significantly enhanced our understanding of Fgf9's role in these processes, providing potential therapeutic targets for related diseases such as NASH-driven HCC, osteoporosis, and epilepsy [1,2,5].

References:

1. Zhang, Lei, Zhang, Qing, Teng, Da, Chang, Yongsheng, Zhang, Huabing. 2023. FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2301166. doi:10.1002/advs.202301166. https://pubmed.ncbi.nlm.nih.gov/37566761/

2. Chen, Mingmei, Liang, Hui, Wu, Min, Wang, Zhugang, Tang, Lingyun. 2024. Fgf9 regulates bone marrow mesenchymal stem cell fate and bone-fat balance in osteoporosis by PI3K/AKT/Hippo and MEK/ERK signaling. In International journal of biological sciences, 20, 3461-3479. doi:10.7150/ijbs.94863. https://pubmed.ncbi.nlm.nih.gov/38993574/

3. Sun, Yidan, Ying, Xiyu, Li, Ruomei, Shi, Jiajun, Chen, Zhenqi. 2022. FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway. In Biomolecules, 12, . doi:10.3390/biom12111639. https://pubmed.ncbi.nlm.nih.gov/36358989/

4. Tang, Lingyun, Chen, Mingmei, Wu, Min, Zhang, Chenping, Wang, Zhugang. 2024. Fgf9 promotes incisor dental epithelial stem cell survival and enamel formation. In Stem cell research & therapy, 15, 293. doi:10.1186/s13287-024-03894-y. https://pubmed.ncbi.nlm.nih.gov/39256850/

5. Guo, Moran, Cui, Can, Song, Xueqin, Duan, Weisong, Li, Chunyan. 2021. Deletion of FGF9 in GABAergic neurons causes epilepsy. In Cell death & disease, 12, 196. doi:10.1038/s41419-021-03478-1. https://pubmed.ncbi.nlm.nih.gov/33608505/