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Development. 2014 Jun;141(12):2402-13. doi: 10.1242/dev.105130. Epub 2014 May 21.

DNMT3L promotes quiescence in postnatal spermatogonial progenitor cells.

Author information

1
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
2
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
3
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
4
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan.
5
Department of Biochemistry, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
6
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan.
7
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo 157-8535, Japan.
8
Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan.
9
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
10
Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei 100, Taiwan.
11
Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
12
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
13
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan Center for Systems Biology, National Taiwan University, Taipei 106, Taiwan Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 106, Taiwan shaupinglin@ntu.edu.tw.

Abstract

The ability of adult stem cells to reside in a quiescent state is crucial for preventing premature exhaustion of the stem cell pool. However, the intrinsic epigenetic factors that regulate spermatogonial stem cell quiescence are largely unknown. Here, we investigate in mice how DNA methyltransferase 3-like (DNMT3L), an epigenetic regulator important for interpreting chromatin context and facilitating de novo DNA methylation, sustains the long-term male germ cell pool. We demonstrated that stem cell-enriched THY1(+) spermatogonial stem/progenitor cells (SPCs) constituted a DNMT3L-expressing population in postnatal testes. DNMT3L influenced the stability of promyelocytic leukemia zinc finger (PLZF), potentially by downregulating Cdk2/CDK2 expression, which sequestered CDK2-mediated PLZF degradation. Reduced PLZF in Dnmt3l KO THY1(+) cells released its antagonist, Sal-like protein 4A (SALL4A), which is associated with overactivated ERK and AKT signaling cascades. Furthermore, DNMT3L was required to suppress the cell proliferation-promoting factor SALL4B in THY1(+) SPCs and to prevent premature stem cell exhaustion. Our results indicate that DNMT3L is required to delicately balance the cycling and quiescence of SPCs. These findings reveal a novel role for DNMT3L in modulating postnatal SPC cell fate decisions.

KEYWORDS:

DNMT3L; Mouse; Proliferation; Quiescence; Spermatogonial progenitor cell

PMID:
24850856
DOI:
10.1242/dev.105130
[Indexed for MEDLINE]
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