Sex Determination and Gonadal Development

ResearchCentre for Endocrinology and Metabolism > Sex Determination and Gonadal Development

3-D-model-testis-cordsSex Determination and Gonadal Development

Research Group Head: Professor Vincent Harley

Intersex variations (also referred to as Disorders of Sex Development), are congenital conditions where development of chromosomal, gonadal, or anatomical sex is atypical. Intersex variations encompass a wide range of conditions, including hypospadias (abnormal urinary opening in males), gonadal dysgenesis (underdeveloped or imperfectly formed gonads), and atypical genitalia and sex reversal (i.e. a congenital inconsistency between a person’s gonads and their phenotype).  Our aim is to identify genes causing intersex variations, and the molecular mechanisms underlying testis and ovary formation in the embryo. We hope to apply this knowledge to improve diagnosis of intersex variations. Approaches include human genetics, as well as molecular, cell and developmental biology.

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Ono, M. and Harley, V. (2013) Disorders of sex development: new genes, new concepts. Nature Reviews Endocrinology 9(2): 79-91.

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 153: 1948-1958

Bernard, P., Ryan, J., Sim, H., Czech, D.P., Sinclair, A.H., Koopman, P. and Harley, V.R. (2012) Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer. Endocrinology 153: 901-912.

Bagheri-Fam, S., Argentaro, A., Svingen, T., Combes, A., Sinclair, A., Koopman, P. and Harley, V.R. (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Human Molecular Genetics 20: 2213-2224.

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.

Sutton, E., Hughes, J., White, S., Sekido, R., Tan, J., Arboleda, V., Rogers, N., Knower, K., Rowley, L., Eyre, H., Rizzoti, K., McAninch, D., Goncalves, J., Slee, J., Turbitt, E., Bruno, D., Bengtsson, H., Harley, V., Vilain, E., Sinclair, A., Lovell-Badge, R. and Thomas, P. (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. Journal of Clinical Investigation 121: 328-341.

Harley, V.R, Layfield, S., Mitchell, C.L., Forwood, J.K, John, A.P., Briggs, L.J., McDowall, S.G., Jans, D.A. (2003) Defective importin  recognition and nuclear import of the sex determining factor SRY are associated with XY sex reversing mutations. Proceedings of the National Academy of Sciences (USA) 100: 7045-7050

Harley, V.R., Jackson, D.I., Hextall, P.J., Hawkins, J.R., Berkovitz, G.D., Sockanathan, S. Lovell-Badge, R., and Goodfellow, P.N. (1992) DNA-binding activity of recombinant SRY from normal males and XY females. Science 255: 453-457.