Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model
Abstract The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-09604-9 |
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| author | Courtney M. Sutton Kohei Umezu Daisuke Mashiko Masahito Ikawa Irina V. Larina Thomas X. Garcia Martin M. Matzuk |
| author_facet | Courtney M. Sutton Kohei Umezu Daisuke Mashiko Masahito Ikawa Irina V. Larina Thomas X. Garcia Martin M. Matzuk |
| author_sort | Courtney M. Sutton |
| collection | DOAJ |
| description | Abstract The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both hPRSS55 rescue lines sired offspring; RES GPI males exhibited partially restored fertility with significantly fewer pups per litter compared to controls, while RES TM males demonstrated fertility comparable to controls. In contrast, T12 RES males remained infertile, exhibiting severe defects in sperm motility and other parameters, despite confirmed transgene mRNA expression. These findings indicate that human PRSS55, particularly when tagged intracellularly, can functionally replace its mouse counterpart, validating the RES TM line as a promising model for testing human PRSS55-targeted contraceptives. The inability of hTMPRSS12 to rescue fertility highlights challenges potentially due to sequence divergence or unconfirmed protein expression levels. |
| format | Article |
| id | doaj-art-14a5a8a2b3d944a2a73d6f3e4d99d381 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-14a5a8a2b3d944a2a73d6f3e4d99d3812025-08-20T03:04:25ZengNature PortfolioScientific Reports2045-23222025-08-0115111210.1038/s41598-025-09604-9Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research modelCourtney M. Sutton0Kohei Umezu1Daisuke Mashiko2Masahito Ikawa3Irina V. Larina4Thomas X. Garcia5Martin M. Matzuk6Center for Drug Discovery, Baylor College of MedicineDepartment of Integrative Physiology, Baylor College of MedicineDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka UniversityDepartment of Integrative Physiology, Baylor College of MedicineCenter for Drug Discovery, Baylor College of MedicineCenter for Drug Discovery, Baylor College of MedicineAbstract The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both hPRSS55 rescue lines sired offspring; RES GPI males exhibited partially restored fertility with significantly fewer pups per litter compared to controls, while RES TM males demonstrated fertility comparable to controls. In contrast, T12 RES males remained infertile, exhibiting severe defects in sperm motility and other parameters, despite confirmed transgene mRNA expression. These findings indicate that human PRSS55, particularly when tagged intracellularly, can functionally replace its mouse counterpart, validating the RES TM line as a promising model for testing human PRSS55-targeted contraceptives. The inability of hTMPRSS12 to rescue fertility highlights challenges potentially due to sequence divergence or unconfirmed protein expression levels.https://doi.org/10.1038/s41598-025-09604-9 |
| spellingShingle | Courtney M. Sutton Kohei Umezu Daisuke Mashiko Masahito Ikawa Irina V. Larina Thomas X. Garcia Martin M. Matzuk Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model Scientific Reports |
| title | Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model |
| title_full | Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model |
| title_fullStr | Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model |
| title_full_unstemmed | Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model |
| title_short | Rescue of male infertility by human PRSS55 in transgenic mice establishes a contraceptive research model |
| title_sort | rescue of male infertility by human prss55 in transgenic mice establishes a contraceptive research model |
| url | https://doi.org/10.1038/s41598-025-09604-9 |
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