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Article

Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells

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Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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Departments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
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Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
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Federal Research Institute for Animal Health, Friedrich-Loeffler-Institute, 31535 Neustadt, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Alexander E. Kalyuzhny
Cells 2021, 10(9), 2265; https://doi.org/10.3390/cells10092265
Received: 7 June 2021 / Revised: 18 August 2021 / Accepted: 25 August 2021 / Published: 31 August 2021
(This article belongs to the Special Issue Male Germline 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 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 Uch-l1−/− mouse model. We confirmed that UCH-L1 is expressed in undifferentiated and early-differentiating spermatogonia in the post-natal mammalian testis. The Uch-l1−/− mice showed reduced testis weight and progressive degeneration of seminiferous tubules. Single-cell transcriptome analysis detected a dysregulated metabolic profile in spermatogonia of Uch-l1−/− compared to wild-type mice. Furthermore, cultured Uch-l1−/− 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. View Full-Text
Keywords: UCH-L1; murine spermatogenesis; germ cell differentiation; metabolic regulation; mitochondrial capacity UCH-L1; murine spermatogenesis; germ cell differentiation; metabolic regulation; mitochondrial capacity
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MDPI and ACS Style

Alpaugh, W.F.; Voigt, A.L.; Dardari, R.; Su, L.; Al Khatib, I.; Shin, W.; Goldsmith, T.M.; Coyle, K.M.; Tang, L.A.; Shutt, T.E.; Klein, C.; Biernaskie, J.; Dobrinski, I. Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells. Cells 2021, 10, 2265. https://doi.org/10.3390/cells10092265

AMA Style

Alpaugh WF, Voigt AL, Dardari R, Su L, Al Khatib I, Shin W, Goldsmith TM, Coyle KM, Tang LA, Shutt TE, Klein C, Biernaskie J, Dobrinski I. Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells. Cells. 2021; 10(9):2265. https://doi.org/10.3390/cells10092265

Chicago/Turabian Style

Alpaugh, Whitney F., 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, and Ina Dobrinski. 2021. "Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells" Cells 10, no. 9: 2265. https://doi.org/10.3390/cells10092265

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