Scientists Identify Key Gene for Male Sex Determination
Loss of the gene Gadd45g results in complete sex reversal of male mice, making them appear female. The scientists at the Institute of Molecular Biology (IMB) in Mainz, Germany, have uncovered a novel signaling cascade, which acts early in development to determine the gonads in males
This discovery sheds light on the genetic network that controls how embryos develop as males or females. The research has just been published in the high-impact journal Developmental Cell.
Research carried out in the laboratory of IMB
Director Professor Christof Niehrs uncovered
that the deletion of just one gene, Gadd45g,
results in male mice with external genitalia that are
indistinguishable from those of female mice.
Furthermore, the internal reproductive organs of
the mutant male mice look like those of females,
indicating that a complete sex reversal has occurred.
"When breeding Gadd45g mutant mice we were
puzzled why we got only females, until we
discovered that some of these females actually
carry a Y-chromosome."
Institute of Molecular Biology
The researchers further showed that Gadd45g exerts its effect by regulating signaling cascades that control the gene Sry, which had previously shown to be a master regulator of male sex development. This study both identifies a new role for Gadd45g and suggests a novel signaling pathway that could have important implications for research into disorders of sexual development.
For male sex organs to develop correctly,
it is essential that the gene Sry is expressed
at high levels within a very narrow
timeframe in the embryo.
The group of Christof Niehrs has now shown
that Gadd45g is expressed in a pattern highly
similar to that of Sry.
The Gadd45g gene is, however, active just before Sry
is turned on. Importantly, in mice lacking Gadd45g,
the Sry gene is not expressed correctly.
This indicates that Gadd45g controls
the expression of this master regulator
and in turn, male development.
The scientists also provide a possible mechanism by which Gadd45g regulates Sry. Their model suggests that Gadd45g binds to and activates key signaling proteins, such as p38, which activate the transcription factor Gata4. When active, this factor binds to and activates the Sry gene. Similar results are co-published in the same issue of Developmental Cell by the group of Andy Greenfield in the UK.
"As outsiders to the field of sex determination we were surprised by how little was known about the regulation of Sry on the molecular level. Our work is a leap forward in the understanding of this fundamental process,” says Niehrs.
Original article: http://www.uni-mainz.de/presse/15869_ENG_HTML.php