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Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells

Yu-Dong Wei Xiao-Min Du Dong-Hui Yang Fang-Lin Ma Xiu-Wei Yu Meng-Fei Zhang Na Li Sha Peng Ming-Zhi Liao Guang-Peng Li Chun-Ling Bai Wei-Shuai Liu Jin-Lian Hua

Yu-Dong Wei, Xiao-Min Du, Dong-Hui Yang, Fang-Lin Ma, Xiu-Wei Yu, Meng-Fei Zhang, Na Li, Sha Peng, Ming-Zhi Liao, Guang-Peng Li, Chun-Ling Bai, Wei-Shuai Liu, Jin-Lian Hua. Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells. Zoological Research, 2021, 42(1): 14-27. doi: 10.24272/j.issn.2095-8137.2020.186
Citation: Yu-Dong Wei, Xiao-Min Du, Dong-Hui Yang, Fang-Lin Ma, Xiu-Wei Yu, Meng-Fei Zhang, Na Li, Sha Peng, Ming-Zhi Liao, Guang-Peng Li, Chun-Ling Bai, Wei-Shuai Liu, Jin-Lian Hua. Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells. Zoological Research, 2021, 42(1): 14-27. doi: 10.24272/j.issn.2095-8137.2020.186

Dmrt1通过抑制TLR4信号通路来调节奶山羊雄性生殖干细胞的免疫反应

doi: 10.24272/j.issn.2095-8137.2020.186

Dmrt1 regulates the immune response by repressing the TLR4 signaling pathway in goat male germline stem cells

Funds: This work was supported by the China National Basic Research Program (2016YFA0100203), National Natural Science Foundation of China (31572399, 32072806, 32072815, 32002246), State Key Lab of Reproductive Regulation & Breeding of Grassland Livestock (SKL-OT-201801), Science and Technology Major Project of Inner Mongolia Autonomous Region of China (ZDZX2018065), and Shaanxi Province Science and Technology Innovation Team (2019TD-036)
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  • 摘要: 雄性生殖干细胞 (male Germ Stem Cell, mGSCs),同样被称作精原干细胞 (Spermatogonial Stem Cells, SSCs),是位于睾丸曲细精管基底膜上,既能通过自我更新维持自身群体数量的稳定,又能在体内定向分化并最终形成精子的一类成体干细胞。雄性生殖干细胞可以作为研究精子发生、减数分裂调控和细胞重编程的一个理想体外模型。Double sex and mab-3 related transcription factor 1 (DMRT1) 基因编码的蛋白质包含一个double sex/mab-3结构域,无论是在脊椎动物或者无脊椎动物中,这个最保守的结构域都会参与个体的性别决定过程。转录因子Dmrt1在奶山羊雄性生殖干细胞(mGSCs)和支持细胞(Sertoli cells)中都存在表达。在这项研究中,我们探究了Dmrt1在奶山羊mGSCs中免疫应答作用。Dmrt1通过募集转录因子Plzf(Promyelocytic Leukemia Zinc Finger,Plzf;又称为zinc finger and BTB domain-containing protein 16,Zbtb16)以抑制Toll样受体4(Toll-like receptor 4,TLR4)依赖性的炎症信号通路和核因子NF- κB的表达,从而降低雄性生殖干细胞中炎症反应的发生。我们在曲细精管中敲低Dmrt1导致了生殖细胞和体细胞的丢失,并发现促炎因子TNFα及IL-6的表达量上调。同时我们发现Dmrt1可以促进mGSCs的自我更新和增殖,并抑制由炎症反应引起的雄性生殖干细胞的凋亡。综合以上结果表明,DMRT1在促进雄性生殖干细胞自我更新及维持睾丸内环境稳态中的重要功能,提供了治疗睾丸生殖缺陷疾病的新思路。
    #Authors contributed equally to this work
  • Figure  1.  Knockdown of Dmrt1 led to degeneration of spermatogenic cells and inflammation in seminiferous tubules

    A: Immunofluorescence staining of Dmrt1 in pSIH-H1-shDmrt1 or pSIH-H1 lentivirus-injected testes. Scale bar: 100 μm. B: Immunofluorescence staining of Dmrt1 in normal mouse testes. Scale bar: 100 μm. C: Percentage of Dmrt1-positive cells in pSIH-H1-shDmrt1 or pSIH-H1 lentivirus-injected testes and normal testes. D: Degeneration of spermatogenic cells in seminiferous tubules following Dmrt1 knockdown. Scale bar: 50 μm. E: Immunohistochemical detection of NF-κB in Dmrt1-knockdown and control testes. Scale bar: 25 μm. F: Immunohistochemical detection of IL-6 in Dmrt1-knockdown and control testes. Scale bar: 25 μm. G: Immunohistochemical detection of TNFα in Dmrt1-knockdown and control testes. Scale bar: 25 μm. H: ELISA of IL-6 in testis-shDmrt1 and testis-H1. I: ELISA of TNFα in testis-shDmrt1 and testis-H1. *: P<0.05; **: P<0.01; ***: P<0.001.

    Figure  2.  Knockdown Dmrt1 induced apoptosis and reduced proliferation of mGSCs

    A: qRT-PCR detection of mRNA levels of inflammatory factors in testis-H1 and testis-shDmrt1. B: Western blotting detection of protein levels of inflammatory factors in testis-H1 and testis-shDmrt1. C: Protein levels were quantified using ImageJ software and normalized to GAPDH. D: Immunofluorescence detection of PCNA and TUNEL assay in testis-H1 and testis-shDmrt1. Scale bar: 100 μm. E: Western blotting detection of protein levels of apoptosis- and proliferation-related genes in testis-H1 and testis-shDmrt1. F: Protein levels were quantified using ImageJ software and normalized to GAPDH. *: P<0.05; **: P<0.01; ***: P<0.001.

    Figure  3.  Transcriptional profiling of Dmrt1-knockdown testes

    A: Volcano plot of expression profiles comparing testis-H1 and testis-shDmrt1. B: GO analysis of DEGs in testis-H1 and testis-shDmrt1. C: KEGG analysis of DEGs in testis-H1 and testis-shDmrt1.

    Figure  4.  Dmrt1 inhibited TLR4 and NF-kB signaling pathways in mGSCs

    A: Immunofluorescence detection of TLR4 in mGSCs-Dmrt1 and mGSCs-shDmrt1. Scale bar: 200 μm. B: Immunofluorescence detection of NF-κB in mGSCs-Dmrt1 and mGSCs-shDmrt1. Scale bar: 200 μm. C: Percentage of TLR4 and NF-κB-positive cells in mGSCs-Dmrt1 and mGSCs-shDmrt1. D: Luciferase activity of pGL3-TLR4 in mGSCs transfected with pCDH-Dmrt1 or pCDH-Plzf, respectively. E: Luciferase activity of pGL3-NF-κB in mGSCs transfected with pCDH-Dmrt1 or pCDH-Plzf, respectively. F: Western blotting for PLZF (top) and DMRT1 (bottom) using IP input lysate and eluates from control IgG, DMRT1 IgG, or PLZF IgG IPs. mGSCs transfected with Dmrt1 plus Plzf-overexpressed plasmids were used for detection. G: Western blotting for PLZF (top) and DMRT1 (bottom) using IP input lysate and eluates from control IgG, DMRT1 IgG, or PLZF IgG IPs. mGSCs transfected with Dmrt1 plus Plzf-overexpressed plasmids, Plzf plus Dmrt1-knockdown plasmids, or Dmrt1 plus Plzf-knockdown plasmids were used for detection. *: P<0.05; **: P<0.01; ***: P<0.001.

    Figure  5.  Dmrt1 repressed inflammation induced by LPS in mGSCs

    A: Protein expression levels of inflammatory factors TLR4 and NF-κB in mGSCs under treatment with different concentrations of LPS. B: Protein levels were quantified using ImageJ software and normalized to GAPDH. C: Protein expression levels of TLR4, NF-κB, and DMRT1 in LPS-mGSCs-pCDH and LPS-mGSCs-Dmrt1. D: Protein levels were quantified using ImageJ software and normalized to GAPDH. E: Immunofluorescence staining of TLR4 in mGSCs-Dmrt1 and mGSCs-shDmrt1 under LPS treatment. Scale bar: 200 μm. F: Immunofluorescence staining of NF-κB in mGSCs-Dmrt1 and mGSCs-shDmrt1 under LPS treatment. Scale bar: 200 μm. G: Percentage of TLR4- and NF-κB-positive cells in Dmrt1-knockdown or Dmrt1-overexpressed mGSCs. H: ELISA of IL-6 and TNFα in mGSCs under treatment with different concentrations of LPS. I: ELISA of IL-6 and TNFα in mGSCs-Dmrt1 and mGSCs-shDmrt1. *: P<0.05; **: P<0.01; ***: P<0.001.

    Figure  6.  Dmrt1 repressed apoptosis and promoted proliferation of mGSCs

    A: Growth curve and population doubling time (PDT) of mGSCs and MSCs under treatment with different concentrations of LPS. B: Flow cytometry of cell cycle in mGSCs and MSCs under LPS treatment (0, 0.5, and 1 μg/mL). C: Flow cytometry of cell apoptosis in mGSCs and MSCs under LPS treatment (0, 0.5, and 1 μg/mL). D: Western blotting of cyclin-D1, PCNA, and caspase-3 in mGSCs under treatment with different concentrations of LPS. E: Protein levels were quantified using ImageJ software and normalized to GAPDH. F: Flow cytometry of cell cycle in LPS-mGSCs, LPS-mGSCs-H1, and LPS-mGSCs-shDmrt1. G: Western blotting of IL-6, PCNA, and cyclin-D1 in LPS-mGSCs-Dmrt1 and LPS-mGSCs-Plzf. H: Protein levels were quantified using ImageJ software and normalized to GAPDH. *: P<0.05; **: P<0.01; ***: P<0.001.

    Figure  7.  Schematic of Dmrt1 repressing immune response but promoting proliferation of mGSCs

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出版历程
  • 收稿日期:  2020-12-10
  • 录用日期:  2021-01-07
  • 网络出版日期:  2021-01-08
  • 刊出日期:  2021-01-18

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