The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Anthony D. Krentz; Mark W. Murphy; Shinseog Kim; Matthew S. Cook; Blanche Capel; Rui Zhu; Angabin Matin; Aaron L. Sarver; Keith L. Parker; Michael D. Griswold; Leendert H.J. Looijenga; Vivian J. Bardwell; David Zarkower

doi:10.1073/pnas.0905431106

The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Anthony D. Krentz, Mark W. Murphy, Shinseog Kim, Matthew S. Cook, Blanche Capel, Rui Zhu, Angabin Matin, Aaron L. Sarver, Keith L. Parker, Michael D. Griswold, Leendert H.J. Looijenga, Vivian J. Bardwell, David Zarkower

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159 Scopus citations

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.

Original language	English (US)
Pages (from-to)	22323-22328
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	52
DOIs	https://doi.org/10.1073/pnas.0905431106
State	Published - Dec 19 2009

Keywords

Embryonal carcinoma
GDNF
Germ cell tumor
Testicular teratoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Krentz, A. D., Murphy, M. W., Kim, S., Cook, M. S., Capel, B., Zhu, R., Matin, A., Sarver, A. L., Parker, K. L., Griswold, M. D., Looijenga, L. H. J., Bardwell, V. J., & Zarkower, D. (2009). The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proceedings of the National Academy of Sciences of the United States of America, 106(52), 22323-22328. https://doi.org/10.1073/pnas.0905431106

Krentz, AD, Murphy, MW, Kim, S, Cook, MS, Capel, B, Zhu, R, Matin, A, Sarver, AL, Parker, KL, Griswold, MD, Looijenga, LHJ, Bardwell, VJ & Zarkower, D 2009, 'The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 52, pp. 22323-22328. https://doi.org/10.1073/pnas.0905431106

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AU - Zhu, Rui

AU - Matin, Angabin

AU - Sarver, Aaron L.

AU - Parker, Keith L.

AU - Griswold, Michael D.

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AU - Zarkower, David

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AB - 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.

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The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

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UN SDGs

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