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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. The pathway is antagonised by the actions of ovarian factors Dax1 and Wnt4.
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
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National Health and Medical Research Council
Outcomes
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Identified novel genes involved in human disorders of sexual development
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Established the molecular pathways that SOX9 and FGFR2 act through during testis development
Selected Publications
Ludbrook, L. Bernard, P., Bagheri-Fam, S., Sekido, R., Wilhelm, D., Lovell-Badge, R. and Harley, V.R. (2012) Excess DAX1 leads to XY ovotesticular DSD in mice by inhibiting Sf1 activation of the testis enhancer of SOX9. Endocrinology, Jan 31. [Epub ahead of print]
Bagheri-Fam, S., Sreenivasan, R., Bernard, P., Knower, K.C., Sekido, R., Lovell-Badge, R., Just, W., and Harley, V.R. Sox9 gene regulation and the loss of the XY/XX sex determining mechanism in the mole vole, Ellobius lutescens. Chromosome Research. Accepted 12 Nov 2011. [Epub ahead of print]
Knower, K.C., Kelly, S., Ludbrook, L.M., Bagheri-Fam, S., Sim, H., Bernard, P., Sekido, R., Lovell-Badge, R. and Harley, V.R. (2011) Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations. PLoS One 6: e17751.
Sim, H., Argentaro, A., Czech, D.P., Bagheri-Fam, S., Sinclair, A.H., Koopman, P.A., Boizet-Bonhoure, B., Poulat, F. and Harley, V.R. (2011) Inhibition of SRY-calmodulin complex formation induces ectopic expression of ovarian cell markers in developing XY gonads. Endocrinology 152: 2883-2893.
Bernard, P. and Harley, V.R. (2010) Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. International Journal of Biochemistry and Cell Biology 42: 400-410.
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.