1. A. D. Krentz, M. W. Murphy, S. Kim, M. S. Cook, B. Capel, R. Zhu, A. Matin, A. L. Sarver, K. L. Parker, M. D. Griswold, L. H. Looijenga, V. J. Bardwell and D. Zarkower (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 106(52): 22323-8.
Abstract Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. Here, we show that in mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas, whereas these tumors do not form in Dmrt1 mutant C57BL/6J mice. Conditional gene targeting indicates that Dmrt1 is required in fetal germ cells but not in Sertoli cells to prevent teratoma formation. Mutant 129Sv germ cells undergo apparently normal differentiation up to embryonic day 13.5 (E13.5), but some cells fail to arrest mitosis and ectopically express pluripotency markers. Expression analysis and chromatin immunoprecipitation identified DMRT1 target genes, whose missexpression may underlie teratoma formation. DMRT1 indirectly activates the GDNF coreceptor Ret, and it directly represses the pluripotency regulator Sox2. Analysis of human germ cell tumors reveals similar gene expression changes correlated to DMRT1 levels. Dmrt1 behaves genetically as a dose-sensitive tumor suppressor gene in 129Sv mice, and natural variation in Dmrt1 activity can confer teratoma susceptibility. This work reveals a genetic link between testicular dysgenesis, pluripotency regulation, and teratoma susceptibility that is highly sensitive to genetic background and to gene dosage. PMID: [20007774]
2. S. Kim, V. J. Bardwell and D. Zarkower (2007) Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation. Dev Biol 307(2): 314-27.
Abstract 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. PMID: [17540358]
3. C. K. Matson, M. W. Murphy, M. D. Griswold, S. Yoshida, V. J. Bardwell and D. Zarkower (2010) The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Dev Cell 19(4): 612-24.
Abstract The switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonial development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm. PMID: [20951351]
Figures for illustrating the function of this protein/gene
Ref: A. D. Krentz, M. W. Murphy, S. Kim, M. S. Cook, B. Capel, R. Zhu, A. Matin, A. L. Sarver, K. L. Parker, M. D. Griswold, L. H. Looijenga, V. J. Bardwell and D. Zarkower (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 106(52): 22323-8. PMID: [20007774]
Ref: A. D. Krentz, M. W. Murphy, S. Kim, M. S. Cook, B. Capel, R. Zhu, A. Matin, A. L. Sarver, K. L. Parker, M. D. Griswold, L. H. Looijenga, V. J. Bardwell and D. Zarkower (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 106(52): 22323-8. PMID: [20007774]
Ref: A. D. Krentz, M. W. Murphy, S. Kim, M. S. Cook, B. Capel, R. Zhu, A. Matin, A. L. Sarver, K. L. Parker, M. D. Griswold, L. H. Looijenga, V. J. Bardwell and D. Zarkower (2009) The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A 106(52): 22323-8. PMID: [20007774]
Function
Transcription factor that plays a key role in male sexdetermination and differentiation by controlling testisdevelopment and male germ cell proliferation. Plays a central rolein spermatogonia by inhibiting meiosis in undifferentiatedspermatogonia and promoting mitosis, leading to spermatogonialdevelopment and allowing abundant and continuous production ofsperm. Acts both as a transcription repressor and activator:prevents meiosis by restricting retinoic acid (RA)-dependenttranscription and repressing STRA8 expression and promotesspermatogonial development by activating spermatogonialdifferentiation genes, such as SOHLH1. Also plays a key role inpostnatal sex maintenance by maintaining testis determination andpreventing feminization: represses transcription of femalepromoting genes such as FOXL2 and activates male-specific genes.May act as a tumor suppressor. May also play a minor role inoogenesis.
Testis-specific. In adult testis, expressed inSertoli cells in all regions of the seminiferous tubules.Expressed dynamically in premeiotic germ cells (spermatogonia),with high expression only in regions of the seminiferous tubulethat are early in the spermatogenic cycle (at protein level).Expressed in all mitotic spermatogonia. Expression decreases withthe onset of spermatogonial differentiation and disappears at theinitiation of meiosis.