Studies in Science and PNAS may overturn dogma of genetically programmed fates for gonadal cells
By Charles Choi | March 31, 2006
Retinoic acid appears to control the timing and perhaps the choice for germ cells in the developing mouse to begin changing into eggs or sperm, scientists report in the March 30 online edition of Science. Their paper, and the recent findings of another group appearing in the Proceedings of the National Academy of Sciences, could force a rethinking of prevailing theories that suggest germ cells have genetically programmed fates.
Instead, germ cells may be "a blank slate that await chemical instructions to tell them which way to go," Science study coauthor Peter Koopman at the University of Queensland in Brisbane told The Scientist.
Whether developing germ cells become male or female depends on when they enter meiosis. If meiosis begins during fetal development, oogenesis is triggered, while delayed meiosis spurs spermatogenesis. It is widely thought that fetal germ cells in both males and females are intrinsically programmed to enter meiosis and trigger oogenesis unless prevented from doing so by a meiosis-inhibiting factor in males that until now had not been identified, Koopman said.
Koopman and his colleagues screened for genes expressed in a sex-specific manner during mouse gonadogenesis and focused on Cyp26b1, the product of which degrades retinoic acid, which in turn regulates the development of many organ systems. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis showed that expression of the gene became male-specific about 12.5 days post coitum.
Koopman and his colleagues found that in male Cyp26b1-knockout mice, germ cells enter meiosis precociously, suggesting CYP26B1 is the meiosis-inhibiting factor in male embryos. The PNAS study similarly found Cyp26b1 is expressed in embryonic mouse testes but not in ovaries, and that an inhibitor of CYP26 enzymes induced expression of pre-meiotic marker Stra8 in the testes. CYP26B1 is the only CYP26 enzyme found in embryonic gonads.
In quantitative RT-PCR experiments, Koopman and his colleagues found exposing male urogenital ridge organ cultures to retinoic acid induced the expression of Stra8 and meiotic progression markers Scp3 and Dmc1, while suppressing the pluripotency marker Oct4. Exposing female urogenital ridge organ cultures to a retinoic acid receptor antagonist prevented the downregulation of Oct4 normally observed in fetal ovaries and substantially decreased Stra8, Scp3 and Dmc1 expression, suggesting retinoic acid is a meiosis-inducing factor. The PNAS study likewise found retinoic acid stimulated Stra8 expression in embryonic mouse testes.
"They have certainly made an important observation in terms of an area of cell cycle control about which we know little, the trigger for entry into meiosis. Being able to putatively identify a signaling pathway we can now begin to dissect is very exciting," Debra Wolgemuth at Columbia University in New York, who did not participate in either study, told The Scientist.
Still, "a lot more research needs to be done to show whether or not the fate of these cells has actually been changed," Wolgemuth cautioned. Experiments should test whether germ cells in males that precociously enter meiosis express male- or female-specific proteins, she said.
William Blaner at Columbia University, who did not participate in either study, suggested future experiments could also examine the expression patterns of enzymes upstream of retinoic acid synthesis to see if they help regulate germ cell meiosis as well and analyze whether the byproducts of CYP26B1's metabolism of retinoic acid act on germ cells too. PNAS study coauthor Michael Griswold at Washington State University in Pullman added that he is analyzing what role retinoic acid plays in spermatogenesis in mice after birth.
Links within this article
D. Secko, "How to spot a primordial germ cell," The Scientist, September 16, 2003.
J. Bowles et al. "Retinoid signaling determines germ cell fate in mice." Science, published online March 30, 2006.
J. Koubova et al. "Retinoic acid regulates sex-specific timing of meiotic initiation in mice." PNAS 103: 2474-9, February 21, 2006.
W.P. Loomis. "Articles Alert." The Scientist, December 26, 1988.