Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells
Spermatogonia are stem and progenitor cells responsible for maintaining mammalian spermatogenesis. Preserving the balance between self-renewal of spermatogonial stem cells (SSCs) and differentiation is critical for spermatogenesis and fertility. Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) is hi...
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MDPI AG
2021-08-01
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| author | Whitney F. Alpaugh Anna L. Voigt Rkia Dardari Lin Su Iman Al Khatib Wisoo Shin Taylor M. Goldsmith Krysta M. Coyle Lin A. Tang Timothy E. Shutt Claudia Klein Jeff Biernaskie Ina Dobrinski |
| author_facet | Whitney F. Alpaugh Anna L. Voigt Rkia Dardari Lin Su Iman Al Khatib Wisoo Shin Taylor M. Goldsmith Krysta M. Coyle Lin A. Tang Timothy E. Shutt Claudia Klein Jeff Biernaskie Ina Dobrinski |
| author_sort | Whitney F. Alpaugh |
| collection | DOAJ |
| description | Spermatogonia are stem and progenitor cells responsible for maintaining mammalian spermatogenesis. Preserving the balance between self-renewal of spermatogonial stem cells (SSCs) and differentiation is critical for spermatogenesis and fertility. Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) is highly expressed in spermatogonia of many species; however, its functional role has not been identified. Here, we aimed to understand the role of UCH-L1 in murine spermatogonia using a <i>Uch-l1<sup>−/−</sup></i> mouse model. We confirmed that UCH-L1 is expressed in undifferentiated and early-differentiating spermatogonia in the post-natal mammalian testis. The <i>Uch-l1<sup>−/−</sup></i> mice showed reduced testis weight and progressive degeneration of seminiferous tubules. Single-cell transcriptome analysis detected a dysregulated metabolic profile in spermatogonia of <i>Uch-l1</i><sup>−/−</sup> compared to wild-type mice. Furthermore, cultured <i>Uch-l1<sup>−/−</sup></i> SSCs had decreased capacity in regenerating full spermatogenesis after transplantation in vivo and accelerated oxidative phosphorylation (OXPHOS) during maintenance in vitro. Together, these results indicate that the absence of UCH-L1 impacts the maintenance of SSC homeostasis and metabolism and impacts the differentiation competence. Metabolic perturbations associated with loss of UCH-L1 appear to underlie a reduced capacity for supporting spermatogenesis and fertility with age. This work is one step further in understanding the complex regulatory circuits underlying SSC function. |
| first_indexed | 2024-03-10T07:49:05Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T07:49:05Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-2bc4e8d785ac4891b89e2a3b020b09ec2023-11-22T12:23:24ZengMDPI AGCells2073-44092021-08-01109226510.3390/cells10092265Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem CellsWhitney F. Alpaugh0Anna L. Voigt1Rkia Dardari2Lin Su3Iman Al Khatib4Wisoo Shin5Taylor M. Goldsmith6Krysta M. Coyle7Lin A. Tang8Timothy E. Shutt9Claudia Klein10Jeff Biernaskie11Ina Dobrinski12Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaFederal Research Institute for Animal Health, Friedrich-Loeffler-Institute, 31535 Neustadt, GermanyDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, CanadaSpermatogonia are stem and progenitor cells responsible for maintaining mammalian spermatogenesis. Preserving the balance between self-renewal of spermatogonial stem cells (SSCs) and differentiation is critical for spermatogenesis and fertility. Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) is highly expressed in spermatogonia of many species; however, its functional role has not been identified. Here, we aimed to understand the role of UCH-L1 in murine spermatogonia using a <i>Uch-l1<sup>−/−</sup></i> mouse model. We confirmed that UCH-L1 is expressed in undifferentiated and early-differentiating spermatogonia in the post-natal mammalian testis. The <i>Uch-l1<sup>−/−</sup></i> mice showed reduced testis weight and progressive degeneration of seminiferous tubules. Single-cell transcriptome analysis detected a dysregulated metabolic profile in spermatogonia of <i>Uch-l1</i><sup>−/−</sup> compared to wild-type mice. Furthermore, cultured <i>Uch-l1<sup>−/−</sup></i> SSCs had decreased capacity in regenerating full spermatogenesis after transplantation in vivo and accelerated oxidative phosphorylation (OXPHOS) during maintenance in vitro. Together, these results indicate that the absence of UCH-L1 impacts the maintenance of SSC homeostasis and metabolism and impacts the differentiation competence. Metabolic perturbations associated with loss of UCH-L1 appear to underlie a reduced capacity for supporting spermatogenesis and fertility with age. This work is one step further in understanding the complex regulatory circuits underlying SSC function.https://www.mdpi.com/2073-4409/10/9/2265UCH-L1murine spermatogenesisgerm cell differentiationmetabolic regulationmitochondrial capacity |
| spellingShingle | Whitney F. Alpaugh Anna L. Voigt Rkia Dardari Lin Su Iman Al Khatib Wisoo Shin Taylor M. Goldsmith Krysta M. Coyle Lin A. Tang Timothy E. Shutt Claudia Klein Jeff Biernaskie Ina Dobrinski Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells Cells UCH-L1 murine spermatogenesis germ cell differentiation metabolic regulation mitochondrial capacity |
| title | Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells |
| title_full | Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells |
| title_fullStr | Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells |
| title_full_unstemmed | Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells |
| title_short | Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells |
| title_sort | loss of ubiquitin carboxy terminal hydrolase l1 impairs long term differentiation competence and metabolic regulation in murine spermatogonial stem cells |
| topic | UCH-L1 murine spermatogenesis germ cell differentiation metabolic regulation mitochondrial capacity |
| url | https://www.mdpi.com/2073-4409/10/9/2265 |
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