Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance
Abstract Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well‐documented previously. This study investigates how busulfan, an alkylating agent that is ofte...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-06-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202200626 |
| _version_ | 1818212337745657856 |
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| author | Laura Thirouard Hélène Holota Mélusine Monrose Manon Garcia Angélique de Haze Christelle Damon‐Soubeyrand Yoan Renaud Jean‐Paul Saru Alessia Perino Kristina Schoonjans Claude Beaudoin David H. Volle |
| author_facet | Laura Thirouard Hélène Holota Mélusine Monrose Manon Garcia Angélique de Haze Christelle Damon‐Soubeyrand Yoan Renaud Jean‐Paul Saru Alessia Perino Kristina Schoonjans Claude Beaudoin David H. Volle |
| author_sort | Laura Thirouard |
| collection | DOAJ |
| description | Abstract Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well‐documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild‐type and Tgr5‐deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders. |
| first_indexed | 2024-12-12T05:46:48Z |
| format | Article |
| id | doaj.art-1c16e21b6be44b36869d7bc07bd1b3b5 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-12T05:46:48Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1c16e21b6be44b36869d7bc07bd1b3b52022-12-22T00:35:46ZengWileyAdvanced Science2198-38442022-06-01917n/an/a10.1002/advs.202200626Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and ChemoresistanceLaura Thirouard0Hélène Holota1Mélusine Monrose2Manon Garcia3Angélique de Haze4Christelle Damon‐Soubeyrand5Yoan Renaud6Jean‐Paul Saru7Alessia Perino8Kristina Schoonjans9Claude Beaudoin10David H. Volle11INSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Bio‐informatic facility Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceLaboratory of Metabolic Signaling Institute of Bioengineering School of Life Sciences Ecole Polytechnique Fédérale de Lausanne Lausanne CH‐1015 SwitzerlandLaboratory of Metabolic Signaling Institute of Bioengineering School of Life Sciences Ecole Polytechnique Fédérale de Lausanne Lausanne CH‐1015 SwitzerlandINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceINSERM U1103 Université Clermont Auvergne CNRS UMR‐6293 GReD Institute Team‐Volle Clermont‐Ferrand F‐63037 FranceAbstract Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well‐documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild‐type and Tgr5‐deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders.https://doi.org/10.1002/advs.202200626chemodrugsgerm cellsGLIS2male fertilitystem cell regenerationTGR5 |
| spellingShingle | Laura Thirouard Hélène Holota Mélusine Monrose Manon Garcia Angélique de Haze Christelle Damon‐Soubeyrand Yoan Renaud Jean‐Paul Saru Alessia Perino Kristina Schoonjans Claude Beaudoin David H. Volle Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance Advanced Science chemodrugs germ cells GLIS2 male fertility stem cell regeneration TGR5 |
| title | Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance |
| title_full | Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance |
| title_fullStr | Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance |
| title_full_unstemmed | Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance |
| title_short | Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance |
| title_sort | identification of a crosstalk among tgr5 glis2 and tp53 signaling pathways in the control of undifferentiated germ cell homeostasis and chemoresistance |
| topic | chemodrugs germ cells GLIS2 male fertility stem cell regeneration TGR5 |
| url | https://doi.org/10.1002/advs.202200626 |
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