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OSR1 disruption contributes to uterine factor infertility via impaired Mullerian 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.

SUBMITTER: Lofrano-Porto A

PROVIDER: S-EPMC10688984 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Lofrano-Porto Adriana A Pereira Sidney Alcântara SA Dauber Andrew A Bloom Jordana Cb JC Fontes Audrey N AN Asimow Naomi N de Moraes Olívia Laquis OL Araujo Petra Ariadne T PAT Abreu Ana Paula AP Guo Michael H MH De Oliveira Silviene F SF Liu Han H Lee Charles C Kuohung Wendy W Coelho Michella S MS Carroll Rona S RS Jiang Rulang R Kaiser Ursula B UB

The Journal of clinical investigation 20231201 23

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 ...[more]

PMID: 37847567

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Project description:BackgroundModern lifestyle has led to an increase in the age at conception. Advanced age is one of the critical risk factors for female-related infertility. It is well known that maternal age positively correlates with the deterioration of oocyte quality and chromosomal abnormalities in oocytes and embryos. The effect of age on endometrial function may be an equally important factor influencing implantation rate, pregnancy rate, and overall female fertility. However, there are only a few published studies on this topic, suggesting that this area has been under-explored. Improving our knowledge of endometrial aging from the biological (cellular, molecular, histological) and clinical perspectives would broaden our understanding of the risks of age-related female infertility.Objective and rationaleThe objective of this narrative review is to critically evaluate the existing literature on endometrial aging with a focus on synthesizing the evidence for the impact of endometrial aging on conception and pregnancy success. This would provide insights into existing gaps in the clinical application of research findings and promote the development of treatment options in this field.Search methodsThe review was prepared using PubMed (Medline) until February 2023 with the keywords such as 'endometrial aging', 'receptivity', 'decidualization', 'hormone', 'senescence', 'cellular', 'molecular', 'methylation', 'biological age', 'epigenetic', 'oocyte recipient', 'oocyte donation', 'embryo transfer', and 'pregnancy rate'. Articles in a language other than English were excluded.OutcomesIn the aging endometrium, alterations occur at the molecular, cellular, and histological levels suggesting that aging has a negative effect on endometrial biology and may impair endometrial receptivity. Additionally, advanced age influences cellular senescence, which plays an important role during the initial phase of implantation and is a major obstacle in the development of suitable senolytic agents for endometrial aging. Aging is also accountable for chronic conditions associated with inflammaging, which eventually can lead to increased pro-inflammation and tissue fibrosis. Furthermore, advanced age influences epigenetic regulation in the endometrium, thus altering the relation between its epigenetic and chronological age. The studies in oocyte donation cycles to determine the effect of age on endometrial receptivity with respect to the rates of implantation, clinical pregnancy, miscarriage, and live birth have revealed contradictory inferences indicating the need for future research on the mechanisms and corresponding causal effects of women's age on endometrial receptivity.Wider implicationsIncreasing age can be accountable for female infertility and IVF failures. Based on the complied observations and synthesized conclusions in this review, advanced age has been shown to have a negative impact on endometrial functioning. This information can provide recommendations for future research focusing on molecular mechanisms of age-related cellular senescence, cellular composition, and transcriptomic changes in relation to endometrial aging. Additionally, further prospective research is needed to explore newly emerging therapeutic options, such as the senolytic agents that can target endometrial aging without affecting decidualization. Moreover, clinical trial protocols, focusing on oocyte donation cycles, would be beneficial in understanding the direct clinical implications of endometrial aging on pregnancy outcomes.

Dataset Information

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

Publications

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

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