Brain gene makes a female embryo develop as male

Australian researchers have discovered that changes in a gene involved in brain development may cord to testis formation and male genital organs in an otherwise female embryos.

Men usually have one Y chromosome and one X chromosome, while females have two X chromosomes.

Lead researcher Melbourne Professor Andrew Sinclair, of the Murdoch Childrens Research Institute and the University of Melbourne, said the breakthrough would improve diagnosis and clinical treatment of patients with disorders of sex development (DSD).

A single gene on the Y, called SRY triggers testis development in early embryos, and when these begin to form, the rest of the embryo is also male.

These conditions occur when the testes or ovaries do not develop in the embryo, causing genital abnormalities in one in 4,500 babies.

However, the Adelaide researchers have discovered a way to make a male mouse without a Y chromosome by activating a single gene called SOX3, in fetal life.

The gene, called SOX3, sits on the X chromosome, and are normally involved in the development of the central nervous system and brain pituitary gland.

SOX3 is known to be important for brain development, but has not previously been shown to trigger the male way.

However, researchers found that mutations that affect the SOX3 gene caused it to be abnormally turned on in embryonic gonads, leading to testis development in human DSD patients and mice.

In a large international collaborative study, they have also shown for the first time that changes in the human version of the same gene is present in some patients with disorders of sexual development.

In men, testicular development regulated by an identical gene on the Y chromosome called SRY.

The results of this work is published online today in the Journal of Clinical Investigation, and will be published in the magazines print version in January 2011.The Y chromosome contains a gene called SRY that acts as a genetic switch to activate the male under way embryonic development, said Professor Paul Thomas from the University of Adelaide School of Molecular&Biomedical Science.

Females have two X chromosomes and therefore does not have an SRY gene.

The SRY genetic switch is unique to mammals and is thought to have evolved from SOX3 gene in early mammalian evolution.

We were confused over how female fetuses may develop testes without SRY gene, Professor Sinclair.

Professor Thomas and his colleagues have generated male mice with two X chromosomes by artificially activating the SOX3 gene in the developing gonads.

Surprisingly, we found that the SOX3 gene could replace the SRY gene in XX female fetuses, resulting in the development of testes, male genitalia and a masculine appearance in these patients.

These reversed XX male mice are completely male in appearance, reproductive structures and behaviors, but are sterile because of an inability to produce sperm, he says.

Professor Sinclair says the discovery could explain one of five XX DSD undiagnosed cases, which will help provide a diagnosis and guide clinical management of patients in the future.

We have long suspected that SOX3 is the evolutionary precursor to SRY gene.

The discovery also gives scientists new insights into the evolution of SRY gene, which is thought to have evolved from SOX3 gene.

By showing that SOX3 activate the male way similar to SRY, we now believe that this is true.

It is believed that changes in gene SOX3 like those seen in these patients DSD must have happened millions of years ago, causing the SOX3 gene is switched on in the gonads and initiate testis development.

This work is a long-standing collaboration between 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.

This mutated gene SOX3 evolved into the Y-linked testis determining gene, SRY.

Dr Lovell-Badge says hes 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 the testes develop.

The study, published today by The Journal of Clinical Investigation, was conducted in collaboration with the University of Adelaide, Women and Childrens Hospital, Adelaide, Prince Henry's Institute for Medical Research, Melbourne, King Edward Memorial Hospital, Perth, University of California , USA, and National Institute for Medical Research, UK.

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 development not only in the SRY, but the X and Y chromosomes.

Just think of all the problems this little gene has caused! he says.

Further research with Professor Andrew Sinclair, the Murdoch Childrens Research Institute in Melbourne and Professor Eric Vilaine at UCLA (University of California Los Angeles) have also shown that changes in the human SOX3 gene is present in some individuals who are XX men.

From a genetic perspective, the cases of XX male sex reversal is particularly exciting, and is poorly understood, says Professor Thomas.

This discovery provides new insights into the genetic causes of disorders of sexual development, which is relatively common in the community.

For the future, will this finding impact on molecular diagnosis of these diseases and, ultimately, help us to develop therapies or technologies to improve clinical outcomes, he said.

Posted on Wednesday, December 29, 2010. Filed under , , . You can follow any responses to this entry through the RSS 2.0

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