Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice
Spermatogonial stem cells (SSCs) are essential for initiating and maintaining normal spermatogenesis, and notably, they have important applications in both reproduction and regenerative medicine. Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive....
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| Language: | English |
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0647 |
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| author | Dai Zhou Bang Liu Lvjun Liu Guangmin Liu Fang Zhu Zenghui Huang Shusheng Zhang Zuping He Liqing Fan |
| author_facet | Dai Zhou Bang Liu Lvjun Liu Guangmin Liu Fang Zhu Zenghui Huang Shusheng Zhang Zuping He Liqing Fan |
| author_sort | Dai Zhou |
| collection | DOAJ |
| description | Spermatogonial stem cells (SSCs) are essential for initiating and maintaining normal spermatogenesis, and notably, they have important applications in both reproduction and regenerative medicine. Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive. In this study, we identified a selective expression of APBB1 in dormant human SSCs. We demonstrated for the first time that APBB1 interacted with KAT5, which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation. Intriguingly, Apbb1−/− mice assumed the disrupted spermatogenesis and markedly reduced fertility. SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation, which resulted in the impaired spermatogenesis. Notably, 4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia (NOA), and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1−/− mice. Additionally, we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis. Collectively, our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility. |
| format | Article |
| id | doaj-art-966420db2d2649b591cc4173f89bf0e1 |
| institution | OA Journals |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-966420db2d2649b591cc4173f89bf0e12025-08-20T01:50:22ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0647Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and MiceDai Zhou0Bang Liu1Lvjun Liu2Guangmin Liu3Fang Zhu4Zenghui Huang5Shusheng Zhang6Zuping He7Liqing Fan8Hunan Provincial Key Laboratory of Regional Hereditary Birth Defect Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha, Hunan 410000, China.Hunan Provincial Key Laboratory of Regional Hereditary Birth Defect Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha, Hunan 410000, China.Hunan Provincial Key Laboratory of Regional Hereditary Birth Defect Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha, Hunan 410000, China.Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, Hunan 410000, China.Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, Hunan 410000, China.Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, Hunan 410000, China.Hunan Provincial Key Laboratory of Regional Hereditary Birth Defect Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha, Hunan 410000, China.Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province; Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University, Hunan 410013, China.Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, Hunan 410000, China.Spermatogonial stem cells (SSCs) are essential for initiating and maintaining normal spermatogenesis, and notably, they have important applications in both reproduction and regenerative medicine. Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive. In this study, we identified a selective expression of APBB1 in dormant human SSCs. We demonstrated for the first time that APBB1 interacted with KAT5, which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation. Intriguingly, Apbb1−/− mice assumed the disrupted spermatogenesis and markedly reduced fertility. SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation, which resulted in the impaired spermatogenesis. Notably, 4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia (NOA), and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1−/− mice. Additionally, we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis. Collectively, our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.https://spj.science.org/doi/10.34133/research.0647 |
| spellingShingle | Dai Zhou Bang Liu Lvjun Liu Guangmin Liu Fang Zhu Zenghui Huang Shusheng Zhang Zuping He Liqing Fan Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice Research |
| title | Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice |
| title_full | Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice |
| title_fullStr | Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice |
| title_full_unstemmed | Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice |
| title_short | Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice |
| title_sort | essential regulation of spermatogonial stem cell fate decisions and male fertility by apbb1 via interaction with kat5 and gdf15 in humans and mice |
| url | https://spj.science.org/doi/10.34133/research.0647 |
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