The FGF9 gene is transcribed to yield mRNA and the mRNA is translated to yield FGF9 protein (inferred from mouse homologs). In the developing testis, FGF9 transcription is activated by SOX9 (inferred from mouse homologs).

SOX9 binds the promoter of the FGF9 gene (inferred from mouse homologs)

The missense mutation C775G in exon 5 of FGFR1 encodes a Pro252R gain-of-function mutation that causes Pfeiffer syndrome, an autosomal dominant disorder characterized by premature fusion of bones in the skull and syndactyly of the hands and feet (Muenke, 1994). FGFR1 P252R binds to FGF1, FGF2, FGF4, and FGF6 with 2-5 fold-enhanced affinity, and with 30-fold affinity to FGF9. The enhanced ligand-affinity of the mutant receptor is the result of an additional set of ligand-receptor hydrogen bonds; in particular for FGF9, the additional receptor contacts are thought to compete with FGF9 autoinhibitory dimerization (Ibrahimi, 2004a). The increase in ligand-binding affinity in the absence of an expansion of ligand binding range is thought to account for the milder limb phenotype of Pfeiffer syndrome relative to FGFR2-mediated Apert syndrome (Yu, 2000; Ibrahimi, 2004b).

Somatic mutations in FGFR1 at P252 have also been identified in melanoma (P252S; Ruhe, 2007) and in lung cancer (P252T; Davies, 2005). Based on analogy to the FGFR1 P252R mutation that is found in Pfeiffer syndrome, these mutations are also predicted to increase the ligand-binding affinity of the receptor and to result in increased signaling, although this remains to be directly demonstrated for the S/T alleles (Ibrahimi, 2004a).

FGFR3 P350R is associated with the development of Muenke syndrome, a milder craniosynostotic condition than Apert Syndrome (Bellus, 1996; Reardon, 1997). This mutation, which falls in the highly conserved Ser-Pro dipeptide in the IgII-IgIII linker, has been shown to increase the affinity of the receptor for its natural ligands, particularly for FGF9 (Ibrahimi, 2004a), without expanding the ligand-binding range of the receptor. This difference, compared to the paralogous FGFR2 S252W and P253R mutations, which bind an expanded range of ligands, is thought to account for the milder phenotype of Muenke Syndrome (Yu, 2000; Ibrahimi, 2004a, b).

Subsequent to SRY expression in the gonadal ridge, the SOX9 gene is transcribed to yield mRNA and the mRNA is translated to yield SOX9 protein (Knower et al. 2011, Croft et al. 2018). SRY and NR5A1 (SF1) bound at the TES enhancer (Knower et al. 2011) and the eALDI enhancer (upstream of the TES enhancer, Croft et al. 2018) of the SOX9 gene initially activate transcription of SOX9 (Knower et al. 2011, Croft et al. 2018, and inferred from mouse homologs). Later, SOX9 and NR5A1 activate the TES enhancer, providing a mechanism for autoregulation (Knower et al. 2011). DMRT1, itself directly activated by SOX9, also directly activates SOX9 (inferred from mouse homologs). FGF9 acting through FGFR2 (inferred from mouse homologs) and Prostaglandin D2 (Malki et al. 2005), the product of PTGDS, activate SOX9 through less well characterized mechanisms.

In humans, primordial germ cells (PGCs) are specified about 2 weeks after fertilization, a time before gastrulation (reviewed in Svingen and Koopman 2013, Mäkelä et al. 2019). PGCs are initially located extraembryonically and then migrate to colonize the gonadal ridges (genital ridges) of the embryo during the fifth week after fertilization. At this time, either ovaries and testes can originate from the gonadal ridges. That is, the cells of the gonadal ridges are initially bipotential and remain bipotential until about 42 days after conception, when transient expression of the SRY gene located on the Y chromosome in male embryos is initiated in some somatic cells of the gonadal primordium (reviewed in Sekido and Lovell-Badge 2013, Barrionuevo et al. 2013, Svingen et al. 2013, Mäkelä et al. 2019).
The transcription factors WT1, GATA4, ZFPM2 (FOG2), and the nuclear receptor NR5A1 (SF1) activate transcription of SRY (Shimamura et al. 1997, Hossain and Saunders 2001, De Santa Barbara et al. 2001, Miyamoto et al. 2008, and inferred from mouse homologs). SRY and NR5A1 then activate transcription of SOX9, one of the master regulators of testis development and maintenance (Knower et al. 2011, Croft et al. 2018, inferred from mouse homologs, reviewed in Gonen and Lovell-Badge 2019). Regulation of genes by SRY and then, when expression of SRY decreases, by SOX9 causes the specification of Sertoli cells that further organize formation of the testis by encasing the primordial germ cells in protocords, which then form fully developed testis cords.
SOX9 directly activates its own promoter to maintain SOX9 expression through development and into adulthood (Croft et al. 2018, and inferred from mouse homologs). SOX9 and GATA4 directly activate DMRT1 (inferred from mouse homologs), which maintains testis specification by maintaining expression of SOX9 and other testis-related genes. DMRT1 also acts to suppress ovarian specification by binding and repressing FOXL2 and WNT4 genes (inferred from mouse homologs). SOX9 directly activates FGF9 (inferred from mouse homologs), which acts via FGFR2 to maintain SOX9 expression, and PTGDS (inferred from mouse homologs), which converts Prostaglandin H2 to Prostaglandin D2, a critical hormone-like lipid that recruits supporting cells to Sertoli cells and acts indirectly to maintain SOX9 expression. SOX9, NR5A1, and GATA4 directly activate AMH (De Santa Barbara et al. 1998, and inferred from mouse homologs), an extracellular signaling molecule which causes regression of the Muellerian duct of the female reproductive system. SOX9 also directly activates many other genes, including DHH (Rahmoun et al. 2017, and inferred from mouse homologs), an intercellular signaling molecule required for testis formation.