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Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells
oleh: 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
Format: | Article |
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Diterbitkan: | MDPI AG 2021-08-01 |
Deskripsi
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.