The Roles of DMRT1 in the Fate Determination and Maintenance of Male Germ Cells
DOI:
https://doi.org/10.54097/9h0phe40Keywords:
DMRT1, Spermatogonial Cells, Spermatogenesis, Transcriptional Regulation, Cell Fate DeterminationAbstract
Spermatogenesis is a highly ordered and evolutionarily conserved biological process, which strictly depends on the precise cell fate determination and long-term maintenance of male germ cells. As one of the most evolutionarily conserved sex-regulatory factors in vertebrates, DMRT1 plays an irreplaceable core role in male gonad development, germ cell fate determination, and the entire process of spermatogenesis. Existing studies mainly focus on its function in testicular support cells, and there is still a lack of systematic understanding of its specific regulatory mechanisms in male germ cells. This paper systematically elaborates on the molecular characteristics and spatiotemporal expression patterns of DMRT1, integrating its key functions in embryonic male germ cell development, spermatogonial stem cell maintenance and renewal, meiosis initiation and progression, and sperm morphogenesis and maturation. It also summarizes the upstream and downstream regulatory networks centered on DMRT1. The goal is to clarify the core value of DMRT1 in the fate determination and maintenance of male germ cells. Furthermore, this paper addresses current research gaps, including unclear epigenetic mechanisms and species differences, and provides a theoretical basis for explaining the pathogenesis of male infertility and identifying potential intervention targets.
Downloads
References
[1] Liu, W., et al. (2024). Microenvironment of spermatogonial stem cells: A key factor in the regulation of spermatogenesis. Stem Cell Research & Therapy, 15(1). https://doi.org/ 10.1186/ s13287-024-03768-9.
[2] Fichtner, A., Nettersheim, D., & Bremmer, F. (2024). Pathogenesis and pathobiology of testicular germ cell tumours: A view from a developmental biological perspective with guidelines for pathological diagnostics. Histopathology, 85(5), 701–715. https://doi.org/10.1111/his.14986.
[3] Raymond, C. S., et al. (2000). Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation.Genes & Development, 14(20), 2587–2595. https://doi.org/ 10. 1101/gad.834100.
[4] Zarkower, D., & Murphy, M. W. (2022). DMRT1: An ancient sexual regulator required for human gonadogenesis. Sex Development, 16(2–3), 112–125. https://doi.org/10.1159/000524787.
[5] Jeng, S. R., et al. (2019). Dmrt1 (doublesex and mab-3-related transcription factor 1) expression during gonadal development and spermatogenesis in the Japanese eel. General and Comparative Endocrinology, 279, 154–163. https://doi.org/10.1016/j.ygcen.2019.04.013.
[6] Augstenová, B., & Ma, W. J. (2025). Decoding Dmrt1: Insights into vertebrate sex determination and gonadal sex differentiation. Journal of Evolutionary Biology, 38(7), 811–831. https://doi.org/ 10. 1093/jeb/vaf048.
[7] Huang, S., Ye, L., & Chen, H. (2017). Sex determination and maintenance: The role of DMRT1 and FOXL2. Asian Journal of Andrology, 19(6), 619–624. https://doi.org/10.4103/aja.aja_40_17.
[8] Ayers, K. L., et al. (2015). DMRT1 is required for Müllerian duct formation in the chicken embryo. Developmental Biology, 400(2), 224–236. https://doi.org/10.1016/j.ydbio.2015.02.013.
[9] Zhao, Y., et al. (2018). In vitro modeling of human germ cell development using pluripotent stem cells. Stem Cell Reports, 10(2), 509–523. https://doi.org/10.1016/j.stemcr.2018.01.019.
[10] Zhang, T., & Zarkower, D. (2017). DMRT proteins and coordination of mammalian spermatogenesis. Stem Cell Research, 24, 195–202. https://doi.org/10.1016/j.scr.2017.08.013.
[11] Irie, N., et al. (2023). DMRT1 regulates human germline commitment. Nature Cell Biology, 25(10), 1439–1452. https://doi.org/10.1038/s41556-023-01227-9.
[12] Ichikawa, K., et al. (2022). Prediction of sex-determination mechanisms in avian primordial germ cells using RNA-seq analysis. Scientific Reports, 12(1), 13528. https://doi.org/10.1038/s41598-022-17663-9.
[13] Kulibin, A. Y., & Malolina, E. A. (2020). Formation of the rete testis during mouse embryonic development. Developmental Dynamics, 249(12), 1486–1499. https://doi.org/10.1002/dvdy.225.
[14] Zhang, X., et al. (2023). ATAC-seq and RNA-seq analysis unravel the mechanism of sex differentiation and infertility in sex reversal chicken. Epigenetics & Chromatin, 16(1), 2. https:// doi. org/10.1186/s13072-023-00483-9.
[15] Ioannidis, J., et al. (2021). Primary sex determination in birds depends on DMRT1 dosage, but gonadal sex does not determine adult secondary sex characteristics. Proceedings of the National Academy of Sciences, 118(10). https://doi.org/10.1073/pnas.2020909118.
[16] Thépot, D. (2021). Sex chromosomes and master sex-determining genes in turtles and other reptiles. Genes, 12(11). https://doi.org/10.3390/genes12111733.
[17] Lee, H. J., et al. (2021). DMRT1 gene disruption alone induces incomplete gonad feminization in chicken. The FASEB Journal, 35(9), e21876. https://doi.org/10.1096/fj.202100488R.
[18] Zhong, Z., et al. (2022). The molecular regulation mechanism of dmrt1-based on the establishment of the testis cell line derived from two-spot puffer Takifugu bimaculatus. Fish Physiology and Biochemistry, 48(6), 1475–1494. https://doi.org/10.1007/s10695-022-01113-4.
[19] Dujardin, E., et al. (2023). DMRT1 is a testis-determining gene in rabbits and is also essential for female fertility. eLife, 12. https://doi.org/10.7554/eLife.83470.
[20] Rahmoun, M., et al. (2017). In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures. Nucleic Acids Research, 45(12), 7191–7211. https://doi.org/10.1093/nar/gkx287.
[21] Xu, C., et al. (2020). Mapping molecular pathways for embryonic Sertoli cells derivation based on differentiation model of mouse embryonic stem cells. Stem Cell Research & Therapy,11(1), 85. https://doi.org/10.1186/s13287-020-01590-4.
[22] Webster, K. A., et al. (2017). Dmrt1 is necessary for male sexual development in zebrafish. Developmental Biology, 422(1), 33–46. https://doi.org/10.1016/j.ydbio.2016.12.008.
[23] Shearwin-Whyatt, L., et al. (2025). AMHY and sex determination in egg-laying mammals. Genome Biology, 26(1), 144. https://doi.org/10.1186/s13059-025-03002-9.
[24] Lovelace, D. L., et al. (2016). The regulatory repertoire of PLZF and SALL4 in undifferentiated spermatogonia. Development, 143(11), 1893–1906. https://doi.org/10.1242/dev.132769.
[25] Barka, I., et al. (2025). DMRT1 haploinsufficiency leads to secondary infertility in XY male rabbits. Biology of Reproduction, 113(2), 450–465. https://doi.org/10.1093/biolre/ioaf112.
[26] Cui, N., et al. (2016). MicroRNA-224 regulates self-renewal of mouse spermatogonial stem cells via targeting DMRT1. Journal of Cellular and Molecular Medicine, 20(8), 1503–1512. https://doi. org/ 10.1111/jcmm.12863.
[27] Zhang, T., et al. (2016). DMRT1 is required for mouse spermatogonial stem cell maintenance and replenishment. PLOS Genetics, 12(9), e1006293. https://doi.org/10.1371/journal.pgen.1006293.
[28] Tan, K., Song, H. W., & Wilkinson, M. F. (2021). RHOX10 drives mouse spermatogonial stem cell establishment through a transcription factor signaling cascade. Cell Reports, 36(3), 109423. https://doi.org/10.1016/j.celrep.2021.109423.
[29] Morimoto, H., et al. (2019). ROS amplification drives mouse spermatogonial stem cell self-renewal. Life Science Alliance, 2(2). https://doi.org/10.26508/lsa.201800267.
[30] Song, W., et al. (2020). PLZF suppresses differentiation of mouse spermatogonial progenitor cells via binding of differentiation associated genes. Journal of Cellular Physiology, 235(3), 3033–3042. https://doi.org/10.1002/jcp.29214.
[31] Perrotta, G., Condrea, D., & Ghyselinck, N. B. (2025). Meiosis and retinoic acid in the mouse fetal gonads: An unforeseen twist. Current Topics in Developmental Biology, 161, 59–88. https:// doi. org/ 10.1016/bs.ctdb.2024.11.003.
[32] Feng, C. W., et al. (2021). Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. Development, 148(5). https://doi.org/10.1242/dev.195674.
[33] Binsila, B. K., et al. (2020). EGF, GDNF, and IGF-1 influence the proliferation and stemness of ovine spermatogonial stem cells in vitro. Journal of Assisted Reproduction and Genetics, 37(10), 2615–2630. https://doi.org/10.1007/s10815-020-01893-4.
[34] Duan, L., et al. (2024). Glial cell line-derived neurotrophic factor (GDNF) is essential for colonization and expansion of turbot (Scophthalmus maximus) germ cells in recipients and in vitro culture. Theriogenology, 214, 1–9. https://doi.org/10.1016/j.theriogenology.2024.09.015.
[35] Mori, Y., et al. (2021). Cdc42 is required for male germline niche development in mice. Cell Reports, 36(7), 109550. https://doi.org/10.1016/j.celrep.2021.109550.
[36] Liu, Z. H., et al. (2018). Diethylstilbestrol arrested spermatogenesis and somatic growth in the juveniles of yellow catfish (Pelteobagrus fulvidraco), a fish with sexual dimorphic growth. Fish Physiology and Biochemistry, 44(3), 789–803. https://doi.org/10.1007/s10695-018-0476-9.
[37] Liu, Q., et al. (2024). Effects of exogenous steroid hormones on growth, body color, and gonadal development in the Opsariichthys bidens. Fish Physiology and Biochemistry, 50(2), 449–461. https://doi.org/10.1007/s10695-024-01270-6.
[38] Wright, W. W. (2022). The regulation of spermatogonial stem cells in an adult testis by glial cell line-derived neurotrophic factor. Frontiers in Endocrinology, 13, 896390. https://doi.org/ 10. 3389/fendo.2022.896390.
[39] Nakagawa, T., et al. (2017). Regulation of mitosis-meiosis transition by the ubiquitin ligase β-TrCP in male germ cells. Development, 144(22), 4137–4147. https://doi.org/10.1242/dev.154325.
[40] Ren, F., et al. (2025). Comprehensive analysis of long non-coding RNA and mRNA expression patterns during seminiferous tubules maturation in Guanzhong dairy goats. BMC Genomics, 26(1), 159. https://doi.org/10.1186/s12864-025-11368-9.
[41] Teves, M. E., & Roldan, E. R. S. (2022). Sperm bauplan and function and underlying processes of sperm formation and selection. Physiological Reviews, 102(1), 7–60. https://doi.org/ 10.1152/ physrev.00013.2021.
[42] Li, T., et al. (2018). Expression and cellular localization of double sex and mab-3 related transcription factor 1 in testes of postnatal Small-Tail Han sheep at different developmental stages. Gene, 642, 467–473. https://doi.org/10.1016/j.gene.2017.11.039.
[43] Ivershina, A., et al. (2026). Integrated analysis of testicular histology, sperm quality, and gene expression (TGFB2, DMRT1) in rooster semen (Gallus gallus domesticus). Animals, 16(2). https:// doi. org/10.3390/ani16020249.
[44] Gao, X., et al. (2025). BDE-209 toxicity: From spermiogenesis to sexual maturity in F1 male mice. Ecotoxicology and Environmental Safety, 297, 118231. https://doi.org/10.1016/ j.ecoenv. 2025. 118231.
[45] Ran, L., et al. (2023). Improving effects of telmisartan on spermatogenic disorder induced by fractionated low-dose irradiation in mice. International Urology and Nephrology, 55(6), 1427–1439. https://doi.org/10.1007/s11255-023-03422-9.
[46] Pan, Z., et al. (2021). Differential expression analysis and identification of sex-related genes by gonad transcriptome sequencing in estradiol-treated and non-treated Ussuri catfish Pseudobagrus ussuriensis. Fish Physiology and Biochemistry, 47(2), 565–581. https://doi.org/10.1007/s10695-021-00929-4.
[47] Zhang, M. F., et al. (2023). Transcription factor Dmrt1 triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility. Zoological Research, 44(3), 505–521. https://doi.org/10.24272/j.issn.2095-8137.2022.425.
[48] Krentz, A. D., et al. (2013). Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line. Developmental Biology, 377(1), 67–78. https://doi.org/10.1016/j.ydbio.2013.02.010.
[49] Lin, Q., et al. (2017). Distinct and cooperative roles of amh and dmrt1 in self-renewal and differentiation of male germ cells in zebrafish. Genetics, 207(3), 1007–1022. https://doi.org/ 10. 1534/genetics.117.202457.
[50] Sun, X., et al. (2023). Transcriptomic analysis of ovarian follicles uncovers the crucial genes relevant to follicle selection and preovulatory hierarchy in hens. Journal of Animal Science, 101. https://doi.org/10.1016/j.jas.2023.04.011.
[51] Liu, X., et al. (2023). Polyvinyl chloride microplastics induce changes in gene expression and organ histology along the HPG axis in Cyprinus carpio var. larvae. Aquatic Toxicology, 258, 106483. https://doi.org/10.1016/j.aquatox.2023.106483.
[52] Ding, Y., et al. (2021). Toxic effects of ZnSe/ZnS quantum dots on the reproduction and genotoxicity of rare minnow (Gobiocypris rarus). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 247, 109065. https://doi.org/10.1016/j.cbpc.2021.109065.
[53] Cui, X., et al. (2025). Effects of treatment with a DNA methyltransferase inhibitor 5-aza-dC on sex differentiation in medaka (Oryzias latipes). International Journal of Molecular Sciences, 26(7). https://doi.org/10.3390/ijms26073214.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
