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Image credit: The Genetics of Sex Determination: Rethinking Concepts and Theories Stanford University

Egg and sperm require lifelong protection

The way the sex of an organism is determined may require lifelong maintenance, as retinoic acid signals can reverse a male germ cell to a female germ cell.

Previous work at the University of Minnesota's Department of Genetics, Cell Biology, and Development found sex determination is not permanent. According to a study published in the journal Developmental Cell, sex-specific factors must perform lifelong work to maintain sexual determination and protect against reprogramming cells from one sex to the other.

Using a mouse model, researchers found the sex of gonadal cells – those cells in the ovaries or testes – require maintenance throughout life. Loss of a single transcription factor can result in the transformation of male cells into female cells.

"DMRT1 [1] in the testis and FOXL2 [2] in the ovary have been identified as key factors responsible for maintaining sexual differentiation. What we asked in this study was how the cells maintain sexual differentiation and why their sex determination requires continuous protection," said David Zarkower, Ph.D., principal author and director of the Developmental Biology Center at the University of Minnesota.

Zarkower's research team took a close look at DMRT1 — a human protein encoded by the DMRT1 gene located at the end of the 9th chromosome. Loss of the DMRT1 gene is associated with incomplete germ cell development leading to infertility, abnormal testicular formation, and/or feminization of that individual.

Research determined DMRT1 partners with the male fetal sex gene - Sox9 - to maintain male sexual determination after birth in a mouse. Part of that work includes turning off (silencing) genes normally involved in female fetal sex determination. This discovery indicates that prenatal sex determination is related to maintenance of lifelong sex determination.

Another notable discovery is DMRT1's ability to limit retinoic acid (RA) signals, therefore preventing RA from activating genes normally involved in female sex determination and female organ development.

"While RA [retinoic acid] signaling between cells is absolutely required for sperm production and male fertility, we found that if DMRT1 is not there to guardian maleness, RA can potentially activate genes and drive male-to-female differentiation.

"This shows cell signaling can transform the identities of the very cells that use it from being male to female. We think other cell types may also require mechanisms allowing them to use critical signaling molecules without becoming reprogrammed."

David Zarkower, Ph.D., principal author, Director, Developmental Biology Center, University of Minnesota.

Highlights
•RA is essential for spermatogenesis but can cause Sertoli cell transdifferentiation
•DMRT1 blocks RA signaling from activating female gonadal genes
•DMRT1 permits cell signaling while protecting from cell fate reprogramming
•Related gene networks control ovary development and transdifferentiation

Summary
Mammalian sex determination initiates in the fetal gonad with specification of bipotential precursor cells into male Sertoli cells or female granulosa cells. This choice was long presumed to be irreversible, but genetic analysis in the mouse recently revealed that sexual fates must be maintained throughout life. Somatic cells in the testis or ovary, even in adults, can be induced to transdifferentiate to their opposite-sex equivalents by loss of a single transcription factor, DMRT1 in the testis or FOXL2 in the ovary. Here, we investigate what mechanism DMRT1 prevents from triggering transdifferentiation. We find that DMRT1 blocks testicular retinoic acid (RA) signaling from activating genes normally involved in female sex determination and ovarian development and show that inappropriate activation of these genes can drive sexual transdifferentiation. By preventing activation of potential feminizing genes, DMRT1 allows Sertoli cells to participate in RA signaling, which is essential for reproduction, without being sexually reprogrammed.

Funding for this project was provided by the National Institutes of Health, through grants 5 R01 GM59152 and 1 F32 GM106484, as well as a National Science Foundation pre-doctoral fellowship. Funding was also provided by the Minnesota Medical Foundation and the French Agence Nationale de la Recherche under the program Inestissements d'Avenir labeled ANR-10-LABX-0030-INRT.

The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school's 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Visit http://www.med.umn.edu to learn more.
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