April 15, 2003
Two Genes Required For Testis Formation
CHICAGO— The sex of newborns is dictated by the X and Y chromosomes—girls are XX whereas boys are XY. However, new research from Northwestern University has shown that normal testis formation depends on two genes: the so-called male-determining Sry gene, found on the Y chromosome 10 years ago, and a gene called Dax1 on the X (female) chromosome.
Based on the findings of a Northwestern University’s Feinberg School of Medicine study, published in the May online Nature Genetics, it now appears that Dax1 is required at several points in embryonic testis development.
Until this study, Sry was the only known sex-determining gene. Dax1 had been widely accepted as an “anti-testis” or ovary-determining gene because patients with a duplication or “double dose” of Dax1 had features of XY sex reversal, a condition in which individuals have the chromosomes of males but the physical attributes of females.
Despite these findings, laboratory studies showed that deletion of the Dax1 gene in mice did not prevent ovarian development but instead revealed an important role in testis development.
Because most XY females do not have Sry mutations, Joshua J. Meeks, Jeffrey Weiss, PhD, research associate professor of medicine, and J. Larry Jameson, MD, PhD, Irving S. Cutter Professor and chair of medicine, hypothesized that other genes are necessary for testis determination. Meeks, who is first author on the article, is an MD/PhD student at the Feinberg School.
Their article described studies in XY sex-reversed mice lacking the Dax1 gene. Embryonic gonads were examined during the period when the bipotential gonad becomes a testis or an ovary.
Meeks and colleagues showed that the gonads of all of the Dax1-deleted XY sex-reversed mice had no testis cords—a central feature of sex determination in males—but had ovaries and external female genitalia and were anovulatory (sterile). Expression of the Sry gene was similar in Dax1-deleted mice and in those in which Dax1 was normal, indicating that sex reversal is not caused by reduced Sry levels in Dax1-deleted mice.
Further, Meeks said, “Sex reversal in the absence of Dax1 occurs subsequent to normal Sry expression, suggesting that Sry and Dax1 are both required for normal testis determination.”
Meeks and colleagues at the medical school have been studying the genetic mutations that cause sex reversal in an effort to reveal much-needed information about how these genes regulate gonad development and to better understand the causes of gonadal dysgenesis and infertility in humans.
The study was supported by a grant from the National Institutes of Health.