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Elife. 2019 Jun 24;8. pii: e46349. doi: 10.7554/eLife.46349.

Single-cell sequencing of neonatal uterus reveals an Misr2+ endometrial progenitor indispensable for fertility.

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Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, United States.
Department of Surgery, Harvard Medical School, Boston, United States.
Stanley Center, Broad Institute of MIT and Harvard, Cambridge, United States.
Department of Pathology, Massachusetts General Hospital, Boston, United States.
Department of Neurobiology, Harvard Medical School, Boston, United States.
Department of Gynecology and Reproductive Biology, Massachussets General Hospital, Boston, United States.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States.


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.


AMH; MIS; Mullerian duct; developmental biology; human; infertility; mesenchyme; mouse; rat; uterus development

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