|Male Mice Created Without Y Chromosome|
|SciMed - Genetics & Genome|
|TS-Si News Service|
|Sunday, 26 December 2010 15:00|
Adelaide, SA, Australia. Scientists have activated an ancient brain gene to create male mice without a Y chromosome, a major step toward fuller understanding of overall human sexual development. Given the provably direct similarities and predictive qualities of the mouse model organism, and the existence of masculine XX humans, the findings provide a near-definitive reset of the Y chromosome's role in human sexual development.
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, an international collaborative team at the University of Adelaide discovered a way of creating a male mouse without a Y chromosome by activating a single gene, called SOX3, in the developing fetus. They also showed 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 findings appear in the Journal of Clinical Investigation (JCI).
The SOX3 gene is a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic brain development and the determination of cell fate. The gene has been known for its importance to brain development but has not previously been shown to be capable of triggering the male pathway."The Y chromosome contains a gene called SRY that functions as a genetic switch to activate the male pathway during embryonic development," says Associate Professor Paul Thomas from the Adelaide School of Molecular & Biomedical Science. "The SRY genetic switch is unique to mammals and is thought to have evolved from the SOX3 gene during early mammalian evolution."
Associate Professor Thomas and his colleagues have generated male mice with two X chromosomes by artificially activating the SOX3 gene in the developing gonads. "These XX male sex reversed mice are completely male in appearance, reproductive structures and behavior, but are sterile due to an inability to produce sperm," he says.
"We have suspected for a long time that SOX3 is the evolutionary precursor gene for SRY. By showing that SOX3 can activate the male pathway in the same way as SRY, we now believe this to be true."
This work is a longstanding collaboration between Associate Professor Thomas and Dr Robin Lovell-Badge at the Medical Research Council (MRC) National Institute for Medical Research (NIMR).
Lovell-Badge discovered the SRY gene in mice more than 20 years ago.Robin Lovell-Badge says he's excited about the findings: "SOX3 normally functions in the development of the nervous system, but it is now clear that a mutation that makes it active in the early gonad can turn it into the switch that makes testes develop.
"It is now very likely that something similar to what has happened in the XX male mice and humans we describe also occurred in our early mammalian ancestors, and this led to the evolution not only of SRY, but of the X and Y chromosomes. Just think of all the trouble this little gene has caused!" he says.
Further collaborative research with Professor Andrew Sinclair at the Murdoch Children's Research Institute in Melbourne and Professor Eric Vilain at UCLA (University of California Los Angeles) has also shown that changes in the human SOX3 gene are present in some individuals who are XX males.
"From a genetic perspective, cases of XX male sex reversal are particularly intriguing and are poorly understood," Associate Professor Thomas says. "This discovery provides new insight into the genetic causes of disorders of sexual development, which are relatively common in the community.
"For the future, this discovery will impact on the molecular diagnosis of these disorders and, ultimately, help us to develop therapies or technologies to improve clinical outcomes," he says.
Participation: InstitutionsCentro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal.
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California USA.
Department of Statistics, University of California, Berkeley, California, USA.
Division of Developmental Genetics, MRC National Institute for Medical Research, London, United Kingdom.
Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, Western Australia, Australia.
Murdoch Children’s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Victoria, Australia.
Prince Henry’s Institute of Medical Research, Melbourne, Victoria, Australia.
School 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.
Women’s and Children’s Hospital, North Adelaide, South Australia, Australia.
CitationIdentification of SOX3 as an XX male sex reversal gene in mice and humans. Edwina Sutton, James Hughes, Stefan White, Ryohei Sekido, Jacqueline Tan, Valerie Arboleda, Nicholas Rogers, Kevin Knower, Lynn Rowley, Helen Eyre, Karine Rizzoti, Dale Mcaninch, Joao Goncalves, Jennie Slee, Erin Turbitt, Damien Bruno, Henrik Bengtsson, Vincent Harley, Eric Vilain, Andrew Sinclair, Robin Lovell-Badge and Paul Thomas. Journal of Clinical Investigation 2010; doi:10.1172/JCI42580
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.
|Last Updated on Saturday, 25 December 2010 13:54|