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Sox9 and Fgfr2 in testis development
Summary
We have shown that SOX9 and FGFR2 are key proteins during male sex determination. To identify the molecular pathways that SOX9 and FGFR2 act through, we are undertaking gene/protein expression analyses in Sox9 and Fgfr2 knockout gonads. We are also exploring the function of FGFR2 after the sex determination phase.
Description
The testes serve important functions during fetal development and adulthood. They produce hormones which stimulate the development of the internal and external male genitalia and are responsible for sperm production within the seminiferous tubules. Perturbations in testis development lead to abnormalities of male sexual development such as gonadal dysgenesis with associated testicular tumours, ambiguous external genitalia, male-to-female sex reversal, and infertility.
Our aim is to identify the underlying molecular and cellular events that cause human disorders of sexual development.
In mammals, the sex-determining region of the Y chromosome gene (Sry) determines the bipotential gonad to develop into a testis rather than into an ovary. In the mouse at embryonic day E11.5 (in humans at 7 week gestation), Sry becomes expressed in bipotential supporting cells (primordial Sertoli/follicle cells) and triggers Sertoli cell fate by initiating the transcription of Sox9 which in turn activates the FGF9/FGFR2-signalling pathway. This leads to increased Sertoli cell proliferation and to the development of testis cords, the future seminiferous tubules. We have established conditional Sox9 and Fgfr2 knockout mice which both show XY male-to-female sex reversal.
To identify the molecular pathways that SOX9 and FGFR2 act through, we are undertaking detailed gene expression analyses on these gonads by immunohistochemistry, in situ hybridisation and RT-PCR.
We have previously shown that FGFR2 expression in pre-Sertoli cells is required for male sex determination. Consequently, the XY gonads develop as ovaries.
Since FGFR2 remains strongly expressed in Sertoli cells during fetal wildtype testis development, we speculate that FGFR2 might also play a crucial role in maintaining Sertoli cell identity. To test this hypothesis we will inactivate Fgfr2 specifically in Sertoli cells after testis formation.
Funding
National Health and Medical Research Council
Outcomes
Identified novel genes involved in human disorders of sexual development
Established the molecular pathways that SOX9 and FGFR2 act through during testis development
Selected Publications
Beverdam, A., Svingen, T., Bagheri-Fam, S., Bernard, P., McClive, P., Robson, M., Khojasteh, M.B., Salehi, M., Sinclair, A.H., Harley, V.R., and Koopman, P. (2009). Sox9-dependent expression of Gstm6 in Sertoli cells during testis development in mice. Reproduction 137:481-486.
Bagheri-Fam, S., Sim, H., Bernard, P., Jayakody, I., Taketo, M.M., Scherer, G. and Harley, V.R. (2008). Loss of Fgfr2 leads to XY gonadal sex reversal. Developmental Biology 314, 71-83.
Barrionuevo, F., Bagheri-Fam, S., Klattig, J., Kist, R., Taketo, M.M., Englert, C. and Scherer, G. (2006). Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biology of Reproduction 74, 195-201.