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How to make a male mouse
According to researchers and their colleagues at the National Institutes of Health at Baylor College of Medicine, Houston, the long-standing belief that an embryo will automatically become female unless male hormones turn on - is false. This discovery appears in the August 18 issue of the journal Science.
Humphrey Hung-Chang Yao PhD, head of the Reproductive Developmental Biology Group at the National Institute of Environmental Health Sciences (NIEHS) — a part of NIH — studies how male and female mouse embryos acquire their sex-specific reproductive systems. Yao said all early-stage mammalian embryos, regardless of sex, contain structures for both male and female reproductive tracts. For a mouse or human to end up with the reproductive tract of only 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 androgen."
Since the 1950s, scientists have believed that androgens produced in embryonic testes, promoted the survival of the male reproductive tract. The scientific consensus favored the theory that every embryo was female by default, only the presence of androgens in female embryos resulted in a male reproductive tract. However, Yao's work demonstrates that female embryos actively promote the elimination of the male tract through the protein COUP-TFII, challenging the original theory.
Their evidence comes from a mouse model created by Yao and his group. These mice lack COUP-TFII in the embryonic structure that develops into the reproductive ducts. But to their surprise, female mouse embryos without COUP-TFII have both male and female ducts. Control (or normal) females with COUP-TFII exhibit only the female duct.
As Yao and his team did not find any evidence of androgen in female mice without COUP-TFII, they conclude that the male reproductive tract in female embryos without COUP-TFIIcan occur without androgen.
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 — having both male and female reproductive tracts.
"This work is just the beginning, many interesting questions remain unanswered," says Zha. "We will continue to study how the embryo develops a functional reproductive system."
Yao's group plans to use mouse models to examine how birth defects of the reproductive system originate. These birth defects lead to disorders of sexual development (DSD), which include common defects, such as cryptorchidism, or undescended testicles, as well as the genetic disorders Klinefelter Syndrome and Turner Syndrome.
"Individuals with disorders of sexual development may have challenges due to the presence of intersex organ systems. With its highly novel approach and unexpected findings, Yao's research has important implications for understanding the potential causes of these conditions."
The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default because the male reproductive tracts (Wolffian ducts) in the female degenerate owing to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex—possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. We thus suggest that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance.
Additional co-authors include: Fei Zhao, Heather L. Franco, Karina F. Rodriguez, Paula R. Brown, Ming-Jer Tsai, Sophia Y. Tsai, Humphrey H.-C. Yao
NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit http://www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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The normal female mouse embryo (top) contains only her female reproductive tract,
highlighted in pink. The female mouse embryo without COUP-TFII (bottom)
has both male (blue) and female (pink) tracts. Image credit: NIEHS.