A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to NIEHS researchers and their colleagues at Baylor College of Medicine, Houston. The discovery, which appeared Aug. 18 in the journal Science, changes the long-standing belief that an embryo will automatically become female unless androgens, or male hormones, in the embryo make it male.
Humphrey Hung-Chang Yao, Ph.D., head of the NIEHS Reproductive Developmental Biology Group, studies how male and female mouse embryos acquire their sex-specific reproductive systems. He said all early-stage mammalian embryos, regardless of their sex, contain structures for both male and female reproductive tracts. For a mouse or human to end up with the reproductive tract of one sex after birth, the other tract has to disintegrate.
"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 androgens," Yao said.
Since the 1950s, scientists have believed that androgens produced by embryonic testes promote the survival of the male reproductive tract. The scientific consensus favored a female by default scenario, in which the absence of androgens in female embryos resulted in the breakdown of the male reproductive tract.
However, Yao’s work demonstrated that female embryos actively promote the elimination of the male tract through the action of COUP-TFII, challenging the female by default theory.
The evidence comes from a mouse model created by Yao and his group. The mice lacked COUP-TFII in an embryonic structure that developed into distinct male and female reproductive ducts. To the surprise of Yao and his visiting fellow Fei Zhao, Ph.D., who is also lead author on the paper, female mouse embryos without COUP-TFII displayed both male and female ducts. Control females with COUP-TFII appropriately exhibited only the female duct (see image above).
Because Yao and his team did not find any evidence of androgen production in female mice without COUP-TFII, they concluded that the presence of the male reproductive tract in female embryos lacking COUP-TFII occurred without androgens.
The study suggests that COUP-TFII has to be present to block the growth of male reproductive tracts. Without COUP-TFII, the mice are born intersex, or having both male and female reproductive tracts.
"This work is just the beginning and many interesting questions remain unanswered," Zhao said. "We will continue to study how the embryo develops a functional reproductive system."
Citation: Zhao F, Franco HL, Rodriguez KF, Brown PR, Tsai MJ, Tsai SY, Yao HHC. 2017. Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357(6352):717–720.