Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background
Autor: | Blanche Capel, Matthew S. Cook, Steven C. Munger, Joseph H. Nadeau |
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Rok vydání: | 2011 |
Předmět: |
Male
Homeobox protein NANOG endocrine system Cell cycle checkpoint Blotting Western Cell Cycle Proteins Biology Mice SOX2 medicine Animals Immunoprecipitation Molecular Biology Adaptor Proteins Signal Transducing Oligonucleotide Array Sequence Analysis Homeodomain Proteins Reverse Transcriptase Polymerase Chain Reaction SOXB1 Transcription Factors Cell Cycle Teratoma Nuclear Proteins Proteins Cell Differentiation Development and Stem Cells Cell Biology 3T3 Cells Nanog Homeobox Protein Cell cycle Cadherins medicine.disease Immunohistochemistry Embryonic stem cell Cell Cycle Gene Mice Mutant Strains Neoplasm Proteins Cell biology DNA-Binding Proteins Germ Cells medicine.anatomical_structure Germ cell tumors Reprogramming Germ cell Developmental Biology |
Zdroj: | Development. 138:23-32 |
ISSN: | 1477-9129 0950-1991 |
Popis: | 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. |
Databáze: | OpenAIRE |
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