OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity
Adriana Lofrano-Porto, … , Rulang Jiang, Ursula B. Kaiser
Adriana Lofrano-Porto, … , Rulang Jiang, Ursula B. Kaiser
Published October 17, 2023
Citation Information: J Clin Invest. 2023;133(23):e161701. https://doi.org/10.1172/JCI161701.
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Research Article Development Reproductive biology

OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity

Abstract

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1–/– embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Authors

Adriana Lofrano-Porto, Sidney Alcântara Pereira, Andrew Dauber, Jordana C.B. Bloom, Audrey N. Fontes, Naomi Asimow, Olívia Laquis de Moraes, Petra Ariadne T. Araujo, Ana Paula Abreu, Michael H. Guo, Silviene F. De Oliveira, Han Liu, Charles Lee, Wendy Kuohung, Michella S. Coelho, Rona S. Carroll, Rulang Jiang, Ursula B. Kaiser

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Figure 7

Postnatal expression of Osr1/Osr1 in the developing murine FRT.

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Postnatal expression of Osr1/Osr1 in the developing murine FRT. (A) Osr1...
(A) Osr1 mRNA is present across a broad range of ages in the mouse uterus, with the highest levels at PND14, followed by a second, smaller increase from PND28 to PND35. Data represent mean ± SEM. Groups with different letters differ significantly from each other (P < 0.05; ANOVA/Tukey) (n = 5/group). (B–I) Osr1-LacZ protein staining (brown) is present primarily in the (B and C) luminal and glandular epithelial (LGE) cells of the mouse uterus, with lower levels in the in the endometrial stroma (ES) and with high levels in the (F and G) oviduct epithelium (OE) of PND30 Osr1-LacZ female mice, but not in the (D and E) LGE cells, ES, and in the (H and I) OE of PND30 WT females, confirming specificity of the LacZ staining. (J–M) Osr1 protein staining (green) is present primarily in the (J and K) luminal and glandular epithelial (LGE) cells of the mouse uterus, with lower levels in the in the endometrial stroma (ES) and with high levels in the (L and M) oviduct epithelium (OE) of both PND30 WT and Osr1-LacZ female mice. B (original magnification, ×10) and C (original magnification, ×20) are derived from the same uterine sample from a PND30 Osr1-LacZ female; D (original magnification, ×10) and C (original magnification, ×20) are derived from the same uterine sample from a PND30 WT female; F (original magnification, ×20) and G (original magnification, ×20) show different regions of the same oviduct sample from a PND30 Osr1-LacZ female; H (original magnification, ×20) and I (original magnification, ×20) show different regions of the same oviduct sample from a PND30 WT female. Scale bars: 100μm.