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

Publication ,  Journal Article
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
Published in: Proc Natl Acad Sci U S A
December 29, 2009

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.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 29, 2009

Volume

106

Issue

52

Start / End Page

22323 / 22328

Location

United States

Related Subject Headings

  • Transcription Factors
  • Testicular Neoplasms
  • Teratoma
  • Spermatogenesis
  • Proto-Oncogene Proteins c-ret
  • Pluripotent Stem Cells
  • Phenotype
  • PTEN Phosphohydrolase
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasm Proteins
 

Citation

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MLA
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Krentz, A. D., Murphy, M. W., Kim, S., Cook, M. S., Capel, B., Zhu, R., … Zarkower, D. (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), 22323–22328. https://doi.org/10.1073/pnas.0905431106
Krentz, Anthony D., Mark W. Murphy, Shinseog Kim, Matthew S. Cook, Blanche Capel, Rui Zhu, Angabin Matin, et al. “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, no. 52 (December 29, 2009): 22323–28. https://doi.org/10.1073/pnas.0905431106.
Krentz AD, Murphy MW, Kim S, Cook MS, Capel B, Zhu R, et al. The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22323–8.
Krentz, Anthony D., et al. “The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency.Proc Natl Acad Sci U S A, vol. 106, no. 52, Dec. 2009, pp. 22323–28. Pubmed, doi: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. The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22323–22328.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 29, 2009

Volume

106

Issue

52

Start / End Page

22323 / 22328

Location

United States

Related Subject Headings

  • Transcription Factors
  • Testicular Neoplasms
  • Teratoma
  • Spermatogenesis
  • Proto-Oncogene Proteins c-ret
  • Pluripotent Stem Cells
  • Phenotype
  • PTEN Phosphohydrolase
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasm Proteins