Sex Reversal Gene: Male Mice Can Be Created Without Y Chromosome Via Ancient Brain Gene
ScienceDaily (Dec. 22, 2010) — Researchers in Australia are a step closer to unraveling the mysteries of human sexual development, following genetic studies that show male mice can be created without a Y chromosome -- through the activation of an ancient brain gene.
This is a mouse from associate professor Paul Thomas' lab. Associate professor Thomas and his colleagues have generated male mice with two X chromosomes by artificially activating the SOX3 gene in the developing gonads. (Credit: Photo bySandra Piltz / © University of Adelaide)
Males usually have one Y chromosome and one X chromosome, while females have two X chromosomes. A single gene on the Y, called SRY, triggers testes development in the early embryo, and once these begin to form, the rest of the embryo also becomes male.
However, Adelaide researchers have discovered a way of creating a male mouse without a Y chromosome by activating a single gene, called SOX3, in the developing fetus. SOX3 is known to be important for brain development but has not previously been shown to be capable of triggering the male pathway.
In a major international collaborative study, they also have shown for the first time that changes in the human version of the same gene are present in some patients with disorders of sexual development.
The results of this work are published online in the Journal of Clinical Investigation, and will be published in the journal's print version in January 2011.
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Identification of SOX3 as an XX male sex reversal gene in mice and humans
Edwina Sutton1, James Hughes1, Stefan White2, Ryohei Sekido3, Jacqueline Tan2, Valerie Arboleda4,Nicholas Rogers1, Kevin Knower5, Lynn Rowley2, Helen Eyre6, Karine Rizzoti3, Dale McAninch1,Joao Goncalves7, Jennie Slee8, Erin Turbitt2, Damien Bruno2, Henrik Bengtsson9, Vincent Harley5,Eric Vilain4, Andrew Sinclair2, Robin Lovell-Badge3 and Paul Thomas1
1School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, Australia.
2Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Victoria, Australia.
3Division of Developmental Genetics, MRC National Institute for Medical Research, London, United Kingdom.
4Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California USA.
5Prince Henry’s Institute of Medical Research, Melbourne, Victoria, Australia.
6Women’s and Children’s Hospital, North Adelaide, South Australia, Australia.
7Centro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal.
8Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, Western Australia, Australia.
9Department of Statistics, University of California, Berkeley, California, USA.
Address correspondence to: Paul Thomas, Level 3, Molecular Life Sciences Building, University of Adelaide, North Terrace, Adelaide, South Australia, 5005 Australia. Phone: 61.8.8303.7047; Fax: 61.8.8303.4362; E-mail: paul.thomas@adelaide.edu.au.
Published December 22, 2010
Received for publication February 8, 2010, and accepted in revised form October 27, 2010.
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome–linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box–containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
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