TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL
Spermatogonial stem cells (SSCs) are the initial cells for the spermatogenesis. Although much progress has been made on uncovering a number of modulators for the SSC fate decisions in rodents, the genes mediating human SSCs remain largely unclear. Here we report, for the first time, that TCF3, a mem...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.695545/full |
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| author | Dai Zhou Dai Zhou Dai Zhou Dai Zhou Dai Zhou Jingyu Fan Zhizhong Liu Zhizhong Liu Ruiling Tang Ruiling Tang Xingming Wang Xingming Wang Hao Bo Hao Bo Fang Zhu Fang Zhu Xueheng Zhao Xueheng Zhao Zenghui Huang Zenghui Huang Liu Xing Liu Xing Ke Tao Ke Tao Ke Tao Han Zhang Han Zhang Hongchuan Nie Hongchuan Nie Huan Zhang Huan Zhang Wenbing Zhu Wenbing Zhu Zuping He Liqing Fan Liqing Fan Liqing Fan Liqing Fan |
| author_facet | Dai Zhou Dai Zhou Dai Zhou Dai Zhou Dai Zhou Jingyu Fan Zhizhong Liu Zhizhong Liu Ruiling Tang Ruiling Tang Xingming Wang Xingming Wang Hao Bo Hao Bo Fang Zhu Fang Zhu Xueheng Zhao Xueheng Zhao Zenghui Huang Zenghui Huang Liu Xing Liu Xing Ke Tao Ke Tao Ke Tao Han Zhang Han Zhang Hongchuan Nie Hongchuan Nie Huan Zhang Huan Zhang Wenbing Zhu Wenbing Zhu Zuping He Liqing Fan Liqing Fan Liqing Fan Liqing Fan |
| author_sort | Dai Zhou |
| collection | DOAJ |
| description | Spermatogonial stem cells (SSCs) are the initial cells for the spermatogenesis. Although much progress has been made on uncovering a number of modulators for the SSC fate decisions in rodents, the genes mediating human SSCs remain largely unclear. Here we report, for the first time, that TCF3, a member of the basic helix-loop-helix family of transcriptional modulator proteins, can stimulate proliferation and suppress the apoptosis of human SSCs through targeting podocalyxin-like protein (PODXL). TCF3 was expressed primarily in GFRA1-positive spermatogonia, and EGF (epidermal growth factor) elevated TCF3 expression level. Notably, TCF3 enhanced the growth and DNA synthesis of human SSCs, whereas it repressed the apoptosis of human SSCs. RNA sequencing and chromatin immunoprecipitation (ChIP) assays revealed that TCF3 protein regulated the transcription of several genes, including WNT2B, TGFB3, CCN4, MEGF6, and PODXL, while PODXL silencing compromised the stem cell activity of SSCs. Moreover, the level of TCF3 protein was remarkably lower in patients with spermatogenesis failure when compared to individuals with obstructive azoospermia with normal spermatogenesis. Collectively, these results implicate that TCF3 modulates human SSC proliferation and apoptosis through PODXL. This study is of great significance since it would provide a novel molecular mechanism underlying the fate determinations of human SSCs and it could offer new targets for gene therapy of male infertility. |
| first_indexed | 2024-12-17T12:44:08Z |
| format | Article |
| id | doaj.art-4b2b662e26ad4341893c7cc4d037aedd |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T12:44:08Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-4b2b662e26ad4341893c7cc4d037aedd2022-12-21T21:47:47ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.695545695545TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXLDai Zhou0Dai Zhou1Dai Zhou2Dai Zhou3Dai Zhou4Jingyu Fan5Zhizhong Liu6Zhizhong Liu7Ruiling Tang8Ruiling Tang9Xingming Wang10Xingming Wang11Hao Bo12Hao Bo13Fang Zhu14Fang Zhu15Xueheng Zhao16Xueheng Zhao17Zenghui Huang18Zenghui Huang19Liu Xing20Liu Xing21Ke Tao22Ke Tao23Ke Tao24Han Zhang25Han Zhang26Hongchuan Nie27Hongchuan Nie28Huan Zhang29Huan Zhang30Wenbing Zhu31Wenbing Zhu32Zuping He33Liqing Fan34Liqing Fan35Liqing Fan36Liqing Fan37Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaCollege of Life Sciences, Hunan Normal University, Changsha, ChinaClinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, ChinaNHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, ChinaDepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, United StatesInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaDepartment of Urology, Hunan Cancer Hospital, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, ChinaInstitute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha, ChinaReproductive & Genetic Hospital of CITIC-Xiangya, Changsha, ChinaClinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, ChinaNHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, ChinaSpermatogonial stem cells (SSCs) are the initial cells for the spermatogenesis. Although much progress has been made on uncovering a number of modulators for the SSC fate decisions in rodents, the genes mediating human SSCs remain largely unclear. Here we report, for the first time, that TCF3, a member of the basic helix-loop-helix family of transcriptional modulator proteins, can stimulate proliferation and suppress the apoptosis of human SSCs through targeting podocalyxin-like protein (PODXL). TCF3 was expressed primarily in GFRA1-positive spermatogonia, and EGF (epidermal growth factor) elevated TCF3 expression level. Notably, TCF3 enhanced the growth and DNA synthesis of human SSCs, whereas it repressed the apoptosis of human SSCs. RNA sequencing and chromatin immunoprecipitation (ChIP) assays revealed that TCF3 protein regulated the transcription of several genes, including WNT2B, TGFB3, CCN4, MEGF6, and PODXL, while PODXL silencing compromised the stem cell activity of SSCs. Moreover, the level of TCF3 protein was remarkably lower in patients with spermatogenesis failure when compared to individuals with obstructive azoospermia with normal spermatogenesis. Collectively, these results implicate that TCF3 modulates human SSC proliferation and apoptosis through PODXL. This study is of great significance since it would provide a novel molecular mechanism underlying the fate determinations of human SSCs and it could offer new targets for gene therapy of male infertility.https://www.frontiersin.org/articles/10.3389/fcell.2021.695545/fullTCF3human spermatogonial stem cellsproliferationapoptosisPODXL |
| spellingShingle | Dai Zhou Dai Zhou Dai Zhou Dai Zhou Dai Zhou Jingyu Fan Zhizhong Liu Zhizhong Liu Ruiling Tang Ruiling Tang Xingming Wang Xingming Wang Hao Bo Hao Bo Fang Zhu Fang Zhu Xueheng Zhao Xueheng Zhao Zenghui Huang Zenghui Huang Liu Xing Liu Xing Ke Tao Ke Tao Ke Tao Han Zhang Han Zhang Hongchuan Nie Hongchuan Nie Huan Zhang Huan Zhang Wenbing Zhu Wenbing Zhu Zuping He Liqing Fan Liqing Fan Liqing Fan Liqing Fan TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL Frontiers in Cell and Developmental Biology TCF3 human spermatogonial stem cells proliferation apoptosis PODXL |
| title | TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL |
| title_full | TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL |
| title_fullStr | TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL |
| title_full_unstemmed | TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL |
| title_short | TCF3 Regulates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells by Targeting PODXL |
| title_sort | tcf3 regulates the proliferation and apoptosis of human spermatogonial stem cells by targeting podxl |
| topic | TCF3 human spermatogonial stem cells proliferation apoptosis PODXL |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.695545/full |
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