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Protein disulfide isomerase is essential for spermatogenesis in mice
Yaqiong Zhang, … , Depei Wu, Yi Wu
Yaqiong Zhang, … , Depei Wu, Yi Wu
Published June 24, 2024
Citation Information: JCI Insight. 2024;9(12):e177743. https://doi.org/10.1172/jci.insight.177743.
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Research Article Cell biology Reproductive biology

Protein disulfide isomerase is essential for spermatogenesis in mice

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Abstract

Spermatogenesis requires precise posttranslational control in the endoplasmic reticulum (ER), but the mechanism remains largely unknown. The protein disulfide isomerase (PDI) family is a group of thiol oxidoreductases responsible for catalyzing the disulfide bond formation of nascent proteins. In this study, we generated 14 strains of KO mice lacking the PDI family enzymes and found that only PDI deficiency caused spermatogenesis defects. Both inducible whole-body PDI-KO (UBC-Cre/Pdifl/fl) mice and premeiotic PDI-KO (Stra8-Cre/Pdifl/fl) mice experienced a significant decrease in germ cells, testicular atrophy, oligospermia, and complete male infertility. Stra8-Cre/Pdifl/fl spermatocytes had significantly upregulated ER stress–related proteins (GRP78 and XBP1) and apoptosis-related proteins (Cleaved caspase-3 and BAX), together with cell apoptosis. PDI deletion led to delayed DNA double-strand break repair and improper crossover at the pachytene spermatocytes. Quantitative mass spectrometry indicated that PDI deficiency downregulated vital proteins in spermatogenesis such as HSPA4L, SHCBP1L, and DDX4, consistent with the proteins’ physical association with PDI in normal testes tissue. Furthermore, PDI served as a thiol oxidase for disulfide bond formation of SHCBP1L. Thus, PDI plays an essential role in protein quality control for spermatogenesis in mice.

Authors

Yaqiong Zhang, Aizhen Yang, Zhenzhen Zhao, Fengwu Chen, Xiaofeng Yan, Yue Han, Depei Wu, Yi Wu

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Figure 3

PDI depletion causes testicular atrophy and oligospermia.

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PDI depletion causes testicular atrophy and oligospermia.
(A) H&E an...
(A) H&E analysis of seminiferous tubules of control and Stra8-Cre/Pdifl/fl testes at P10, P12, and P14. Scale bars: 50 μm. (B) H&E-stained testes and epididymal sections in adult control and Stra8-Cre/Pdifl/fl mice. Scale bars: 50 μm. (C) Immunofluorescence staining of SYCP3 in testes of control and Stra8-Cre/Pdifl/fl mice at 8 weeks old (mean ± SEM, n = 3, **P < 0.01, Student’s t test). Scale bar: 50 μm. (D) FITC-labeled PNA was used to examine acrosomes at different developmental stages in adult male Pdifl/fl and Stra8-Cre/Pdifl/fl mice. Scale bar: 50 μm. DNA was counterstained with DAPI. Higher magnifications of the boxed areas on the right show tubule cross-sections at the punctate Golgi (stages I–III), cap (stages IV–VI), and crescent (stages VII–VIII) and acrosome located at the top of the nucleus (stages IX–XII) phases. (E) Sperm counts from adult control and Stra8-Cre/Pdifl/fl mice (mean ± SEM, n = 3, **P < 0.01, Student’s t test).

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