# FGF9

## Overview
Fibroblast growth factor 9 (FGF9) is a gene that encodes the protein fibroblast growth factor 9, a member of the fibroblast growth factor family, which is known for its involvement in a wide range of biological processes, including cell growth, development, and tissue repair. The FGF9 protein functions as a signaling molecule that interacts with specific fibroblast growth factor receptors (FGFRs), particularly FGFR2 and FGFR3, to mediate its effects. It is characterized by its ability to form homodimers, which play a crucial role in regulating its receptor binding and activity. FGF9 is involved in various physiological processes, such as neuroprotection, embryogenesis, and the regulation of cell proliferation, particularly in the human uterine endometrium. Mutations in the FGF9 gene have been linked to skeletal disorders, including multiple synostoses syndrome, highlighting its significance in bone and joint development (Wu2009Multiple; Hecht1995Identification; Tsai2002Fibroblast).

## Structure
Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family, characterized by its unique molecular structure and receptor-binding properties. The primary structure of FGF9 includes specific amino acid sequences that contribute to its functional domains. The secondary structure of FGF9 consists of alpha-helices and beta-sheets, forming a core unit similar to other FGFs, with a root-mean-square deviation (RMSD) of 1.0 Å compared to FGF1 and FGF2 (Hecht2001Structure).

The tertiary structure of FGF9 reveals a symmetric dimer, stabilized by hydrophobic contacts, hydrogen bonds, and salt bridges. This dimerization is crucial for its autoinhibitory function, as it occludes receptor-binding sites, thereby regulating its biological activity (Hecht2001Structure; Kalinina2009Homodimerization). The quaternary structure involves the assembly of these dimers, which can dissociate to allow receptor binding (Hecht2001Structure).

FGF9 undergoes post-translational modifications, such as N-glycosylation, which is essential for its secretion and function (Miyakawa1999A). The protein also features unique receptor- and heparin-binding interfaces, distinct from other FGFs, contributing to its specific receptor interactions and cell selectivity (Hecht2001Structure).

## Function
Fibroblast growth factor 9 (FGF9) is a critical protein involved in various cellular processes, particularly in the human uterine endometrium. It is primarily expressed in endometrial stromal cells and plays a significant role in their proliferation, especially during the late proliferative phase of the menstrual cycle. This phase coincides with increased levels of 17β-estradiol, which induces FGF9 expression, highlighting its role as a downstream effector of estrogen-mediated proliferation (Tsai2002Fibroblast).

FGF9 functions through an autocrine/paracrine mechanism, with limited diffusion from its synthesis site, and does not stimulate epithelial cell proliferation. This specificity is attributed to the differential expression of FGF receptors, with FGFR2IIIc and FGFR3IIIc being abundant in stromal cells, while FGFR2IIIb is primarily in epithelial cells (Tsai2002Fibroblast).

Beyond the uterus, FGF9 is involved in various biological processes, including neuroprotection, cell proliferation, and embryogenesis. It acts as a potent mitogen and survival factor for nerve cells, indicating its broader role in cell growth and survival across different tissues (Tsai2002Fibroblast).

## Clinical Significance
Mutations in the FGF9 gene are associated with multiple synostoses syndrome (SYNS), a condition characterized by joint fusions and skeletal abnormalities. A specific missense mutation, S99N, in FGF9 has been identified as a cause of SYNS3, a subtype of the syndrome. This mutation impairs the FGF9-FGFR3 signaling pathway, crucial for normal skeletal and joint development, by reducing the binding affinity of FGF9 to its receptor FGFR3. This leads to impaired chondrocyte proliferation and differentiation, enhanced osteogenic differentiation, and matrix mineralization, contributing to the pathology of SYNS (Tang2017A; Wu2009Multiple).

The S99N mutation also affects the MAPK and Wnt/b-catenin signaling pathways, resulting in decreased expression of genes essential for chondrogenesis, such as Sox6 and Sox9, and downregulation of Gdf5, a gene important for joint development (Tang2017A; Wu2009Multiple). Another mutation, p.Arg62Gly, has been linked to craniosynostosis and multiple synostoses, affecting FGF9's ability to bind FGFR3 and activate the MAPK pathway, which is crucial for osteogenic growth (Rodriguez‐Zabala2017FGF9). These mutations highlight the critical role of FGF9 in bone and joint development and its involvement in skeletal disorders.

## Interactions
Fibroblast growth factor 9 (FGF9) is known for its interactions with fibroblast growth factor receptors (FGFRs), particularly FGFR2 and FGFR3, where it acts as a high-affinity, heparin-dependent ligand. FGF9 binds more strongly to FGFR3 compared to FGFR2, and this interaction is crucial for its biological functions, including cell proliferation and differentiation (Hecht1995Identification). The binding of FGF9 to these receptors is facilitated by heparan sulfate proteoglycans, which provide additional binding sites (Hecht2001Structure).

FGF9 also interacts with integrin αvβ3, a cell adhesion receptor, which is essential for its signaling functions. This interaction is specific and requires the presence of Mn2+ ions. A mutant form of FGF9, R108E, which is defective in integrin binding, acts as a dominant-negative antagonist, inhibiting the signaling pathways activated by wild-type FGF9. This suggests that integrin binding is critical for FGF9's role in cell signaling and migration (Chang2023FGF9).

FGF9 forms homodimers, which can regulate its receptor binding and diffusion in the extracellular matrix. This dimerization occludes key receptor binding sites, acting as an autoregulatory mechanism to modulate its activity (Kalinina2009Homodimerization).


## References


[1. (Miyakawa1999A) Kazuko Miyakawa, Kiyotaka Hatsuzawa, Tsutomu Kurokawa, Masahiro Asada, Tomoko Kuroiwa, and Toru Imamura. A hydrophobic region locating at the center of fibroblast growth factor-9 is crucial for its secretion. Journal of Biological Chemistry, 274(41):29352–29357, October 1999. URL: http://dx.doi.org/10.1074/jbc.274.41.29352, doi:10.1074/jbc.274.41.29352. This article has 43 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.274.41.29352)

2. (Chang2023FGF9) FGF9, a potent mitogen, is a new ligand for integrin αvβ3, and the FGF9 mutant defective in integrin binding acts as an antagonist. This article has 1 citations.

[3. (Tsai2002Fibroblast) S.-J. Tsai. Fibroblast growth factor-9 is an endometrial stromal growth factor. Endocrinology, 143(7):2715–2721, July 2002. URL: http://dx.doi.org/10.1210/en.143.7.2715, doi:10.1210/en.143.7.2715. This article has 8 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/en.143.7.2715)

[4. (Kalinina2009Homodimerization) Juliya Kalinina, Sara A. Byron, Helen P. Makarenkova, Shaun K. Olsen, Anna V. Eliseenkova, William J. Larochelle, Mohanraj Dhanabal, Steven Blais, David M. Ornitz, Loren A. Day, Thomas A. Neubert, Pamela M. Pollock, and Moosa Mohammadi. Homodimerization controls the fibroblast growth factor 9 subfamily’s receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix. Molecular and Cellular Biology, 29(17):4663–4678, September 2009. URL: http://dx.doi.org/10.1128/mcb.01780-08, doi:10.1128/mcb.01780-08. This article has 37 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.01780-08)

[5. (Hecht1995Identification) Dalit Hecht, Nives Zimmerman, Mark Bedford, Aaron Avivi, and Avner Yayon. Identification of fibroblast growth factor 9 (fgf9) as a high affinity, heparin dependent ligand for fgf receptors 3 and 2 but not for fgf receptors 1 and 4. Growth Factors, 12(3):223–233, January 1995. URL: http://dx.doi.org/10.3109/08977199509036882, doi:10.3109/08977199509036882. This article has 80 citations and is from a peer-reviewed journal.](https://doi.org/10.3109/08977199509036882)

[6. (Hecht2001Structure) H. J. Hecht, R. Adar, B. Hofmann, O. Bogin, H. Weich, and A. Yayon. Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces. Acta Crystallographica Section D Biological Crystallography, 57(3):378–384, March 2001. URL: http://dx.doi.org/10.1107/s0907444900020813, doi:10.1107/s0907444900020813. This article has 23 citations.](https://doi.org/10.1107/s0907444900020813)

[7. (Tang2017A) Lingyun Tang, Xiaolin Wu, Hongxin Zhang, Shunyuan Lu, Min Wu, Chunling Shen, Xuejiao Chen, Yicheng Wang, Weigang Wang, Yan Shen, Mingmin Gu, Xiaoyi Ding, Xiaolong Jin, Jian Fei, and Zhugang Wang. A point mutation in fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Human Molecular Genetics, 26(7):1280–1293, February 2017. URL: http://dx.doi.org/10.1093/hmg/ddx029, doi:10.1093/hmg/ddx029. This article has 26 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddx029)

[8. (Wu2009Multiple) Xiao-lin Wu, Ming-min Gu, Lei Huang, Xue-song Liu, Hong-xin Zhang, Xiao-yi Ding, Jian-qiang Xu, Bin Cui, Long Wang, Shun-yuan Lu, Xiao-yi Chen, Hai-guo Zhang, Wei Huang, Wen-tao Yuan, Jiang-ming Yang, Qun Gu, Jian Fei, Zhu Chen, Zhi-min Yuan, and Zhu-gang Wang. Multiple synostoses syndrome is due to a missense mutation in exon 2 of fgf9 gene. The American Journal of Human Genetics, 85(1):53–63, July 2009. URL: http://dx.doi.org/10.1016/j.ajhg.2009.06.007, doi:10.1016/j.ajhg.2009.06.007. This article has 64 citations.](https://doi.org/10.1016/j.ajhg.2009.06.007)

[9. (Rodriguez‐Zabala2017FGF9) Maria Rodriguez‐Zabala, Miriam Aza‐Carmona, Carlos I. Rivera‐Pedroza, Alberta Belinchón, Isabel Guerrero‐Zapata, Jimena Barraza‐García, Elena Vallespin, Min Lu, Angela del Pozo, Marc J. Glucksman, Fernando Santos‐Simarro, and Karen E. Heath. Fgf9 mutation causes craniosynostosis along with multiple synostoses. Human Mutation, 38(11):1471–1476, July 2017. URL: http://dx.doi.org/10.1002/humu.23292, doi:10.1002/humu.23292. This article has 23 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.23292)