Brain gene a trigger for determining gender

December 22, 2010

University of Adelaide researchers 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.

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 today in the Journal of Clinical Investigation, and will be published in the journal's print version in January 2011.

"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 University of Adelaide's 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 National Institute for Medical Research in London, who discovered the SRY gene in mice more than 20 years ago.

Dr 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.
-end-


University of Adelaide

Related Chromosomes Articles from Brightsurf:

Cancer's dangerous renovations to our chromosomes revealed
Cancer remodels the architecture of our chromosomes so the disease can take hold and spread, new research reveals.

Y chromosomes of Neandertals and Denisovans now sequenced
An international research team led by Martin Petr and Janet Kelso of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has determined Y chromosome sequences of three Neandertals and two Denisovans.

Female chromosomes offer resilience to Alzheimer's
Women live longer than men with Alzheimer's because their sex chromosomes give them genetic protection from the ravages of the disease.

New protein complex gets chromosomes sorted
Researchers from the University of Tsukuba have identified a novel protein complex that regulates Aurora B localization to ensure that chromosomes are correctly separated during cell division.

Breaking up is hard to do (especially for sex chromosomes)
A team of scientists at the Sloan Kettering Institute has discovered how the X and Y chromosomes find one another, break, and recombine during meiosis even though they have little in common.

Exchange of arms between chromosomes using molecular scissors
The CRISPR/Cas molecular scissors work like a fine surgical instrument and can be used to modify genetic information in plants.

How small chromosomes compete with big ones for a cell's attention
Scientists at the Sloan Kettering Institute have solved the puzzle of how small chromosomes ensure that they aren't skipped over during meiosis, the process that makes sperm and egg.

GPS for chromosomes: Reorganization of the genome during development
The spatial arrangement of genetic material within the cell nucleus plays an important role in the development of an organism.

Extra chromosomes in cancers can be good or bad
Extra copies of chromosomes are typical in cancerous tumor cells, but researchers taking a closer look find that some extra copies promote cancer growth while others actually inhibit cancer metastasis.

X marks the spot: recombination in structurally distinct chromosomes
A recent study from the laboratory of Stowers Investigator Scott Hawley, PhD, has revealed more details about how the synaptonemal complex performs its job, including some surprising subtleties in function.

Read More: Chromosomes News and Chromosomes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.