David Zarkower and Vivian Bardwell, professors of genetics, cell biology and development, are co-authors of a new paper that extends the timeline for sex determination. Zarkower, Bardwell and colleagues showed that a specific gene (Dmrt1) can single-handedly reprogram cell identity well past the early stages of development, upending assumptions about the malleability of sex determination.
"The presumption had been that the sex determination decision was made in the embryonic gonad, leading to either a testis or an ovary, and the decision was final," says Zarkower. "That turns out not to be the case in either sex."
In mice, Dmrt1 is required for male gonadal differentiation in somatic cells and germ cells. Dmrt1 also maintains male gonadal sex after birth. Its loss, even in adult mice, can trigger sexual fate reprogramming in which male Sertoli cells turn into their female equivalents – granulosa cells – and testicular tissue reorganizes to a more ovarian structure. In a previous study, Zarkower found that in male mice lacking Dmrt1, Sertoli cells of the testes turned into granulosa cells.
“We’ve been studying this gene for a long time and we knew that it was important for testis development in vertebrates,” says Zarkower. “It has long been assumed that if someone has a sex development disorder, it occurs early on when sex is being determined.” The study suggests a surprising level of plasticity in that process and shows that turning on even one inappropriate gene can overturn the sex determination decision.
The findings are a first step toward a clearer understanding of the mechanisms involved in determining cell fate, an area of interest to researchers developing treatments for neurodegenerative disease, cancer and other conditions. A better understanding of how Dmrt1 does what it does could provide insight into how to efficiently reprogram cell fates for therapeutic purposes.
The paper, published in February in the online edition of Current Biology, is titled “Sexual Cell-Fate Reprogramming in the Ovary by DMRT1.”
— Stephanie Xenos