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Developmental Biology - Infertility

A Source of Infertility?

Mullerian cells required for a healthy uterus...

The timing of cell differentiation when the uterus is forming, not only helps us understand how to maintain uterine health, it explains some forms of female - and male - infertility. Led by investigators at Massachusetts General Hospital (MGH), a research team has uncovered just how critical Mullerian cells are to a functioning uterus.

Mullerian cells are defined by their production (or expression) of a receptor called Mullerian Inhibiting Substance (Misr2+), which is known to be secreted by testes of male embryos in order to prevent cell structures that might otherwise become female reproductive organs. Beginning in the fourth week of development, the urogenital system arises from urogenital ridges forming on each side of the primitive aorta or heart. The nephrogenic ridge is the part of the urogenital ridge that will form our urinary system. Urine begins being excreted into the amniotic cavity towards the end of the first trimester (weeks 11 to 12) and is a major component of amniotic fluid.

Although not surprised that Misr2+ cells are inhibiting formation of a uterus in males, researchers were surprised the exact same cell system supports formation of a uterus in females. These findings are published in eLife.
"The fate of these reproductive gatekeeper cells in females, in the absence of MIS, was unknown. In this study, we found in females these cells continue to express a receptor to MIS, past the period of sexual differentiation in mice, rats, and humans. Furthermore, we show in rodents, these cells retain sensitivity to MIS, even after birth."

David Pépin PhD, Assistant Molecular Biologist, MGH and Assistant Professor, Surgery, Harvard Medical School and senior author.

Administering MIS to rodents in the first week following birth, interfers with uterine development and leads to infertility later. Pépin: "This suggests the period of response to sexual differentiation signals in mammals may not be as restricted as previously thought."

To uncover more details, the team analyzed cells in the uterus of newborn rodents following MIS treatment, and discovered key cell types expected to contribute to the uteral endometrium lining were missing. Investigators believe the missing cells were blocked from differentiating into endometrial cells after being exposed to MIS.
"In the absence of these cells, a large number of important signals are disrupted, leading to abnormal uterine development. This period of fetal development is so critical for specification of uterine layers, exposure to MIS even for just a few days following birth leads to irrecoverable infertility later in life, with femaie adults having a thin uterus made up almost entirely of smooth uterine muscle tissue called the myometrium."

Hatice Duygu Saatcioglu, Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston; Department of Surgery, Harvard Medical School, Boston, Massasschusetts, USA; and first author on the study.

Patricia K. Donahoe, MD, a coauthor and director of surgical research laboratories at MassGeneral Hospital for Children (MGHfC), herself a longtime investigator of MIS functions, notes how these results help explain how some female infertility is caused by very early fetal problems arising when the fetus was still forming.

"Finding cells marked by Misr2 allows for more investigation of how these cells can contribute to uterine pathologies causing infertility," explains Donahoe.

Some of the study's findings may also be relevant to men, as there is a rare disorder called the persistent Mullerian duct syndrome. These men have normal male reproductive organs and normal male external genitalia, but upon examination, are also found to have a uterus and fallopian tubes.

The Mullerian ducts are the anlagen of the female reproductive tract, which regress in the male fetus in response to MIS. This process is driven by subluminal mesenchymal cells expressing Misr2, which trigger the regression of the adjacent Mullerian ductal epithelium. In females, these Misr2+ cells are retained, yet their contribution to the development of the uterus remains unknown. Here, we report that subluminal Misr2+ cells persist postnatally in the uterus of rodents, but recede by week 37 of gestation in humans. Using single-cell RNA sequencing, we demonstrate that ectopic postnatal MIS administration inhibits these cells and prevents the formation of endometrial stroma in rodents, suggesting a progenitor function. Exposure to MIS during the first six days of life, by inhibiting specification of the stroma, dysregulates paracrine signals necessary for uterine development, eventually resulting in apoptosis of the Misr2+ cells, uterine hypoplasia, and complete infertility in the adult female.

Hatice Duygu Saatcioglu, Motohiro Kano, Heiko Horn, Lihua Zhang, Wesley Samore, Nicholas Nagykery, Marie-Charlotte Meinsohn, Minsuk Hyun, Rana Suliman, Joy Poulo, Jennifer Hsu, Caitlin Sacha, Dan Wang, Guangping Gao, Kasper Lage, Esther Oliva, Mary E Morris Sabatini, Patricia K Donahoe, David Pépin.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

O.B. and E.R. designed the study. K.S., K.T., and R.L. contributed to concept and study design. Zebrafish work was performed by K.T. and E.R. M.S. performed FACS sorting of zebrafish PGCs. Methyl-seq and RNA-seq library preparation and sequencing was carried out by K.S. K.S. analysed the data with input from O.B. AS analysis was performed by M.I. K.S and O.B. wrote the manuscript with input from all authors. All authors discussed the results and commented on the manuscript.

Competing interests The authors declare no competing interests. Return to top of page.

Jul 30 2019   Fetal Timeline   Maternal Timeline   News  

Misr2+ Development
Mullerian inhibiting substance receptor-2 (MIS) is found in a specific mesenchymal cell
surrounding the Mullerian duct of fetal urogenital ridges in both male and female fetuses.
In male embryos, secretion of MIS (the ligand of Misr2) by newly forming testes
causes Misr2+ mesenchymal cells to regress these Mullerian duct epithelium cells.
In female embryos, Misr2+ mesenchymal cells continue dividing, creating
the uterine endometrial stromal layers. If female embryos are exposed to MIS
in their first week of uterine development, these progenitor cells will die
instead of developing into endometrial layers, causing future infertility.

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