March 2001

From Washington University School of Medicine

Deleting gene changes sex of mice

St. Louis, March 22, 2001 — Scientists have identified the first growth factor linked to sex determination. Deleting the gene for fibroblast growth factor 9 (Fgf9), a protein important in development, produced mice that had a female reproductive system even though they had a Y chromosome, which normally creates males. Although other genes are known to influence gender, this is the first example of a gene that has been conserved during evolution. Therefore, Fgf9 might play a critical role in sex determination and the development of the reproductive system in a wide variety of animals.

The results are published in the March 23 issue of the journal Cell. David M. Ornitz, M.D., Ph.D., professor of molecular biology and pharmacology at Washington University School of Medicine in St. Louis, led the study. The first authors were Jennifer S. Colvin, Ph.D., a student in the school’s M.D./Ph.D. program, and Rebecca P. Green, M.D., Ph.D., a former postdoctoral fellow in molecular biology and pharmacology and now an instructor in pediatrics. The research was completed in collaboration with Duke University Medical Center.

Fibroblast growth factors regulate cell growth and cell migration and therefore are integral to organ development. The research team initially developed mice lacking the Fgf9 protein to explore its effects on organs such as the lungs. Because the animals die at birth, the scientists didn’t pay attention to the ratio of males to females. When they finally took inventory, they were shocked.

"We were looking for the prostate gland in newborn animals, but we couldn’t find it," Ornitz says. Examining the animals’ genes, Ornitz and colleagues discovered that half of the mice were indeed genetically male, even though they had underdeveloped testes or lacked any male reproductive organs. "We concluded that Fgf9 helps determine male gender during embryonic development," Ornitz says.

Other genes, such as Sry, are thought to induce male development in humans. But they are not found in all mammals. The discovery that a fibroblast growth factor — a protein conserved across species — plays a role in sex determination opens the field for discovering mechanisms. Currently, 22 fibroblast growth factors are known.

"The bulk of patients with disorders that affect sex determination have not been accounted for using previously identified genes such as Sry," says Ornitz. "In the distant future, our understanding of the role of Fgf9 may lead to a better understanding of embryonic development and sex determination disorders, which hopefully will guide new therapies."

Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell, 104:6, 875-889, March 23, 2001.

Funding from Monsanto/Searle/Pharmacia Inc., the Genentech Foundation for Growth and Development, the National Institutes of Health and the National Science Foundation supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.












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