Kim S, Bardwell VJ, Zarkower D. Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation. Dev Biol 307: 314-327

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Developmental Biology (Impact Factor: 3.55). 08/2007; 307(2):314-27. DOI: 10.1016/j.ydbio.2007.04.046
Source: PubMed


Genes containing the DM domain, a conserved DNA binding motif first found in Doublesex of Drosophila and mab-3 of Caenorhabditis elegans, regulate sexual differentiation in multiple phyla. The DM domain gene Dmrt1 is essential for testicular differentiation in vertebrates. In the mouse, Dmrt1 is expressed in pre-meiotic germ cells and in Sertoli cells, which provide essential support for spermatogenesis. Dmrt1 null mutant mice have severely dysgenic testes in which Sertoli cells and germ cells both fail to differentiate properly after birth. Here we use conditional gene targeting to identify the functions of Dmrt1 in each cell type. We find that Dmrt1 is required in Sertoli cells for their postnatal differentiation, and for germ line maintenance and for meiotic progression. Dmrt1 is required in germ cells for their radial migration to the periphery of the seminiferous tubule where the spermatogenic niche will form, for mitotic reactivation and for survival beyond the first postnatal week. Thus Dmrt1 activity is required autonomously in the Sertoli and germ cell lineages, and Dmrt1 activity in Sertoli cells is also required non-autonomously to maintain the germ line. These results demonstrate that Dmrt1 plays multiple roles in controlling the remodeling and differentiation of the juvenile testis.

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    • "The doublesex (dsx) and male abnormal-3 (mab-3) related transcription factor (DMRT) gene family consists of 8 member genes, which are conserved among vertebrates and widely involved in developmental processes including somitogenesis, nervous system development and gonadal differentiation (Zarkower, 2013). Interestingly, Dmrt1, the most well-known member of this family, has recently been identified as being involved in regulating male fetal germ cell proliferation and pluripotency , and controlling the mitosis/meiosis decision in adult mouse spermatogonia (Raymond et al., 2000; Kim et al., 2007a; Krentz et al., 2009; Matson et al., 2010; Matson and Zarkower, 2012). In the mouse ovary, Dmrt1 has been shown to directly activate the transcription of Stra8 (Krentz et al., 2011). "
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    ABSTRACT: We identified three doublesex and mab-3-related transcription factors (DMRT) that were sexually differentially expressed in human fetal gonads and present in the ovaries at the time of meiotic initiation. These were also identified in murine embryonic female germ cells. Among these, we focused on DMRTA2 (DMRT5), whose function is unknown in the developing gonads, and clarified its role in human female fetal germ cells, using an original xenograft model. Early human fetal ovaries (8 to 11 weeks post- fertilization) were grafted into nude mice. Grafted ovaries developed normally, with no apparent overt changes, when compared to ungrafted ovaries at equivalent developmental stages. Appropriate germ cell density, mitotic /meiotic transition, markers of meiotic progression and follicle formation were evident. Four weeks after grafting, mice were treated with siRNA, specifically targeting human DMRTA2 mRNA. DMRTA2 inhibition triggered an increase in undifferentiated FUT4-positive germ cells and a decrease in the percentage of meiotic γH2AX-positive germ cells, when compared with mice that were injected with control siRNA. Interestingly, the expression of markers associated with pre-meiotic germ cell differentiation was also impaired, as was the expression of DMRTB1 (DMRT6) and DMRTC2 (DMRT7). This study reveals, for the first time, the requirement of DMRTA2 for normal human female embryonic germ cell development. DMRTA2 appears to be necessary for proper differentiation of oogonia, prior to entry into meiosis, in the human species. Additionally, we developed a new model of organ xenografting, coupled with RNA interference, which provides a useful tool for genetic investigations of human germline development.
    Molecular Human Reproduction 07/2014; 20(10). DOI:10.1093/molehr/gau058 · 3.75 Impact Factor
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    • "The indel mutation frequency within each individual was estimated by quantifying the band intensity of the restriction enzyme digestion. meiosis initiation, and germ-cell survival (Kim et al. 2007; Matson et al. 2010). Therefore, frameshift deletions in Dmrt1 in tilapia germ cells probably affect their development , meiosis, and maturation in tilapia. "
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    ABSTRACT: Studies of gene function in non-model animals have been limited by the approaches available for eliminating gene function. The CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR associated) system has recently become a powerful tool for targeted genome editing. Here, we report the use of the CRISPR/Cas9 system to disrupt selected genes, including nanos2, nanos3, dmrt1 and foxl2, with efficiencies as high as 95%. In addition, mutations in dmrt1 and foxl2 induced by CRISPR/Cas9 were efficiently transmitted through the germline to F1. Obvious phenotypes were observed in the G0 generation after mutation of germ cell or somatic cell specific genes. For example, loss of Nanos2 and Nanos3 in XY and XX fish resulted in germ cell-deficient gonads as demonstrated by GFP labeling and Vasa staining, respectively, while masculinization of somatic cells in both XY and XX gonads was demonstrated by Dmrt1 and Cyp11b2 immunohistochemistry and by up-regulation of serum androgen levels. Our data demonstrate that targeted, heritable gene editing can be achieved in tilapia, providing a convenient and effective approach for generating loss-of-function mutants. Further, our study shows the utility of the CRISPR/Cas9 system for genetic engineering in non-model species like tilapia, and potentially many other teleost species.
    Genetics 04/2014; 197(2). DOI:10.1534/genetics.114.163667 · 5.96 Impact Factor
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    • "In humans, a deletion of the region of chromosome 9p containing Dmrt1 results in testicular dysgenesis (Raymond et al. 1999b, 2000). Dmrt1 null mutant mice have severely dysgenic testes in which both Sertoli cells and germ cells fail to differentiate properly after birth (Kim et al. 2007). In the chicken, the reduction in Dmrt1 protein expression in ovo leads to the feminization of the embryonic gonads in genetic males (Smith et al. 2009). "
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    ABSTRACT: The Dmrt genes encode a large family of transcription factors with a conserved zinc finger-like DNA-binding DM domain. The function of Dmrt1, one of the family members, in sexual development has been well studied in invertebrates and vertebrates. In the present study, the full-length cDNA of Dmrt1 was isolated from the testis of Sebastes schlegeli. The full-length cDNA of S. schlegeli Dmrt1 (SsDmrt1) was 1,587 bp and contained a 189-bp 5' UTR, a 489-bp 3' UTR and a 909-bp open reading frame, which encoded 302 amino acids with a conserved DM domain and an male-specific motif domain. Phylogenetic analysis showed the evolutionary relationships of SsDmrt1 with other known Dmrt genes in fish and tetrapods. Several transcriptional factor-binding sites in the 5' promoter were identified that might regulate SsDmrt1 expression. Quantitative real-time PCR analysis indicated that SsDmrt1 was expressed in all of the inspected larval developmental stages from 1 to 35 days after birth and that the level of expression gradually decreased. The expression of SsDmrt1 in adult gonads was sexually dimorphic with extremely high expression in the testis, but very low expression in the ovary. No expression was detected in other tissues. Using in situ hybridization, we demonstrated that SsDmrt1 was specifically expressed in the germ cells of both the testis and the ovary. Thus, our results suggest that SsDmrt1 may have an important role in the differentiation of both the testis and the ovary of S. schlegeli.
    Fish Physiology and Biochemistry 02/2014; 40(4). DOI:10.1007/s10695-014-9921-z · 1.62 Impact Factor
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