TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility
Abstract Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation,...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-86848-5 |
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| author | Elijah Edmondson Takahito Kimura Eunmi Hwang Minjun Kim Andrew Warner Yuelin Zhu Li Zhao Yanlin Yu Xuguang Zhu Maria Hernandez Noemi Kedei Sheue-yann Cheng |
| author_facet | Elijah Edmondson Takahito Kimura Eunmi Hwang Minjun Kim Andrew Warner Yuelin Zhu Li Zhao Yanlin Yu Xuguang Zhu Maria Hernandez Noemi Kedei Sheue-yann Cheng |
| author_sort | Elijah Edmondson |
| collection | DOAJ |
| description | Abstract Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTHα patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TRα1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility. |
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| id | doaj-art-5f41be840b0a476886c4d3c7b3e88e18 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-5f41be840b0a476886c4d3c7b3e88e182025-02-02T12:18:04ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-025-86848-5TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertilityElijah Edmondson0Takahito Kimura1Eunmi Hwang2Minjun Kim3Andrew Warner4Yuelin Zhu5Li Zhao6Yanlin Yu7Xuguang Zhu8Maria Hernandez9Noemi Kedei10Sheue-yann Cheng11Frederick National Laboratory for Cancer ResearchNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthFrederick National Laboratory for Cancer ResearchNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthNational Cancer Institute, National Institutes of HealthAbstract Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTHα patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TRα1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility.https://doi.org/10.1038/s41598-025-86848-5Thyroid hormone receptor α1Female reproductionResistance to thyroid hormoneKLF9Spatial transcriptomicsEndometrial metaplasia |
| spellingShingle | Elijah Edmondson Takahito Kimura Eunmi Hwang Minjun Kim Andrew Warner Yuelin Zhu Li Zhao Yanlin Yu Xuguang Zhu Maria Hernandez Noemi Kedei Sheue-yann Cheng TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility Scientific Reports Thyroid hormone receptor α1 Female reproduction Resistance to thyroid hormone KLF9 Spatial transcriptomics Endometrial metaplasia |
| title | TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility |
| title_full | TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility |
| title_fullStr | TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility |
| title_full_unstemmed | TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility |
| title_short | TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility |
| title_sort | trα1 mutant suppresses klf9 to cause endometrial metaplasia with ectopic il 33 expression leading to uterine fibrosis and infertility |
| topic | Thyroid hormone receptor α1 Female reproduction Resistance to thyroid hormone KLF9 Spatial transcriptomics Endometrial metaplasia |
| url | https://doi.org/10.1038/s41598-025-86848-5 |
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