Fgfrl1, or fibroblast growth factor receptor like 1, is the fifth member of the FGFR family. It contains three extracellular Ig-like domains but lacks the protein tyrosine kinase domain, having a short intracellular tail with a histidine-rich motif instead. Fgfrl1 binds to FGF ligands and heparin with high affinity, and is involved in regulating cell proliferation (negatively) and cell differentiation (positively). It contributes to the complexity of the FGF signaling system and is essential in various biological processes [1].

Gene-targeted deletion of Fgfrl1 in mice leads to perinatal death due to diaphragm alterations and bilateral kidney agenesis, highlighting its essential role in kidney development [1]. Mice lacking the Ig2 or Ig3 domain of Fgfrl1 die within 24 h after birth, with Ig3-deficient mice completely lacking metanephric kidneys, suggesting these domains are crucial for kidney growth via regulation of nephrogenesis [4]. In humans, a frameshift mutation in FGFRL1 is associated with craniosynostosis, indicating its role in bone formation [1]. Also, FGFRL1 is associated with height, hypertension, and osteoporosis in the Korean population, and FGFRL1-related genes may contribute to these traits [2]. In small-cell lung cancer, high FGFRL1 expression is associated with chemoresistance, and knockdown increases chemosensitivity by regulating the ENO1-PI3K/Akt pathway [3].

In conclusion, Fgfrl1 plays essential roles in kidney development, bone formation, and is associated with multiple physiological and disease-related processes such as height determination, hypertension, osteoporosis, and cancer chemoresistance. The study of Fgfrl1 knockout mouse models has been crucial in revealing its functions in these biological processes and disease conditions.

References:

1. Trueb, Beat. 2010. Biology of FGFRL1, the fifth fibroblast growth factor receptor. In Cellular and molecular life sciences : CMLS, 68, 951-64. doi:10.1007/s00018-010-0576-3. https://pubmed.ncbi.nlm.nih.gov/21080029/

2. Cho, Hye-Won, Jin, Hyun-Seok, Eom, Yong-Bin. 2022. FGFRL1 and FGF genes are associated with height, hypertension, and osteoporosis. In PloS one, 17, e0273237. doi:10.1371/journal.pone.0273237. https://pubmed.ncbi.nlm.nih.gov/35980984/

3. Chen, Rui, Li, Deyu, Zheng, Meng, Guo, Linlang, Fang, Shun. 2020. FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1. In Journal of cellular and molecular medicine, 24, 2123-2134. doi:10.1111/jcmm.14763. https://pubmed.ncbi.nlm.nih.gov/31957179/

4. Gerber, Simon D, Beauchamp, Philippe, Zhuang, Lei, Villiger, Peter M, Trueb, Beat. 2020. Functional domains of the FgfrL1 receptor. In Developmental biology, 461, 43-54. doi:10.1016/j.ydbio.2020.01.003. https://pubmed.ncbi.nlm.nih.gov/31923383/