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Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background.

Publication ,  Journal Article
Cook, MS; Munger, SC; Nadeau, JH; Capel, B
Published in: Development
January 2011

Human germ cell tumors show a strong sensitivity to genetic background similar to Dnd1(Ter/Ter) mutant mice, where testicular teratomas arise only on the 129/SvJ genetic background. The introduction of the Bax mutation onto mixed background Dnd1(Ter/Ter) mutants, where teratomas do not typically develop, resulted in a high incidence of teratomas. However, when Dnd1(Ter/Ter); Bax(-/-) double mutants were backcrossed to C57BL/6J, no tumors arose. Dnd1(Ter/Ter) germ cells show a strong downregulation of male differentiation genes including Nanos2. In susceptible strains, where teratomas initiate around E15.5-E17.5, many mutant germ cells fail to enter mitotic arrest in G0 and do not downregulate the pluripotency markers NANOG, SOX2 and OCT4. We show that DND1 directly binds a group of transcripts that encode negative regulators of the cell cycle, including p27(Kip1) and p21(Cip)(1). P27(Kip1) and P21(Cip1) protein are both significantly decreased in Dnd1(Ter/Ter) germ cells on all strain backgrounds tested, strongly suggesting that DND1 regulates mitotic arrest in male germ cells through translational regulation of cell cycle genes. Nonetheless, in C57BL/6J mutants, germ cells arrest prior to M-phase of the cell cycle and downregulate NANOG, SOX2 and OCT4. Consistent with their ability to rescue cell cycle arrest, C57BL/6J germ cells overexpress negative regulators of the cell cycle relative to 129/SvJ. This work suggests that reprogramming of pluripotency in germ cells and prevention of tumor formation requires cell cycle arrest, and that differences in the balance of cell cycle regulators between 129/SvJ and C57BL/6 might underlie differences in tumor susceptibility.

Duke Scholars

Published In

Development

DOI

EISSN

1477-9129

Publication Date

January 2011

Volume

138

Issue

1

Start / End Page

23 / 32

Location

England

Related Subject Headings

  • Teratoma
  • SOXB1 Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proteins
  • Oligonucleotide Array Sequence Analysis
  • Nuclear Proteins
  • Neoplasm Proteins
  • Nanog Homeobox Protein
  • Mice, Mutant Strains
  • Mice
 

Citation

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ICMJE
MLA
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Cook, M. S., Munger, S. C., Nadeau, J. H., & Capel, B. (2011). Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background. Development, 138(1), 23–32. https://doi.org/10.1242/dev.057000
Cook, Matthew S., Steven C. Munger, Joseph H. Nadeau, and Blanche Capel. “Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background.Development 138, no. 1 (January 2011): 23–32. https://doi.org/10.1242/dev.057000.
Cook MS, Munger SC, Nadeau JH, Capel B. Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background. Development. 2011 Jan;138(1):23–32.
Cook, Matthew S., et al. “Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background.Development, vol. 138, no. 1, Jan. 2011, pp. 23–32. Pubmed, doi:10.1242/dev.057000.
Cook MS, Munger SC, Nadeau JH, Capel B. Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background. Development. 2011 Jan;138(1):23–32.
Journal cover image

Published In

Development

DOI

EISSN

1477-9129

Publication Date

January 2011

Volume

138

Issue

1

Start / End Page

23 / 32

Location

England

Related Subject Headings

  • Teratoma
  • SOXB1 Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proteins
  • Oligonucleotide Array Sequence Analysis
  • Nuclear Proteins
  • Neoplasm Proteins
  • Nanog Homeobox Protein
  • Mice, Mutant Strains
  • Mice