Insights into how female embryos develop

The normal female mouse embryo (top) contains only the female reproductive tract, highlighted in pink. The female mouse embryo without COUP-TFII (bottom) has both male, in blue, and female reproductive tracts.NIEHS

After the egg of a mouse or other mammal is fertilized, it divides over and over until an embryo begins to form. Each step from egg to fully formed embryo is precisely coordinated. Scientists have been studying the complex factors that enable cells within different types of tissues to communicate with each other and drive embryo formation.

A key step in embryo development is making either a male or female reproductive system. At first, rudimentary tissues for both male and female reproductive tracts are present. In males, the rudimentary female tissue disintegrates and the tissue that will become the adult male reproductive tract develops. In females, the opposite happens: the male tissue degenerates and the female tissue develops into the adult female reproductive tract. In the 1950s, studies showed that male hormones called androgens drive the process that develops male reproductive tract tissue. Scientists assumed that female embryos lost the male tissue because they lacked androgen.

Dr. Humphrey Hung-Chang Yao at NIH’s National Institute of Environmental Health Sciences (NIEHS) led a research team with colleagues at Baylor College of Medicine to investigate how female mouse embryos acquire a female reproductive system. The work was also supported by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Heart, Lung, and Blood Institute (NHLBI). Results were published on August 18, 2017, in Science.

The team created genetically modified mice to study the development of the female embryonic reproductive tract. The mutant mice lacked COUP-TFII, a protein involved in development, in the embryonic structure that develops into the male and female reproductive tracts. As expected, only the female reproductive tract was present in the normal female embryos. To the researchers' surprise, the female mouse embryos without COUP-TFII had both male and female tracts.

The team didn't find any evidence of androgen production in female mice lacking COUP-TFII. In addition, when they used a drug to block undetected androgens that might be present, the mutant female embryos still had male reproductive tracts. They concluded that the presence of the male reproductive tract in female embryos lacking COUP-TFII occurs without androgen.

This finding suggests that COUP-TFII is required to actively block growth of the male reproductive system. It overturns the old assumption that an embryo will automatically become female unless androgens in the embryo make it male. The team is now studying other factors involved in this process.

“I learned in graduate school that androgens are needed to maintain the male reproductive tract, but our work finds that maintenance of the male reproductive tract can be achieved without androgen,” Yao says. The research team will continue to use mouse models to study the development of disorders of sexual development, such as conditions that result in the presence of both male and female reproductive systems.