Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 14, Pages 6210-6215Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914448107
Keywords
germline transmission; spermatogenesis; stem cell; cyclin-dependent kinase inhibitor; self-renewal
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Funding
- Genome Network Project
- Japan Science and Technology Agency
- Program for Promotion of Basic and Applied Researches for Innovation in Biooriented Industry
- Ministry of Health, Labour, and Welfare
- Senri Life Science Foundation
- Novartis Foundation (Japan) for the Promotion of Science
- Astellas Foundation for Research on Metabolic Disorders
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- Grants-in-Aid for Scientific Research [22790379, 20062006] Funding Source: KAKEN
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Spermatogonial stem cells (SSCs) undergo self-renewal division to support spermatogenesis. Although several positive regulators of SSC self-renewal have been identified, little is known about the mechanisms that negatively regulate SSCs. Here we developed a novel transplantation assay for SSCs and demonstrate that p21 and p27 cyclin-dependent kinase inhibitors play critical roles in SSC self-renewal and differentiation. Overexpression of p21 or p27 abrogated proliferation of cultured SSCs in vitro, and their expression levels were downregulated by exogenous self-renewal signals. In contrast, no apparent defects were found in p21 or p27-deficient SSCs by spermatogonial transplantation. However, competitive spermatogonial transplantation with WT SSCs revealed that the loss of either gene causes distortion of germline transmission: p21-deficiency facilitated mutant offspring production, whereas germline transmission was limited by p27-deficiency. Serial transplantation also showed that the loss of p27, but not p21, decreases secondary colony formation, suggesting that appropriate amounts of p27 are necessary for sustaining SSC self-renewal. Thus, p21 and p27 cyclin-dependent kinase inhibitors play critical roles in germline transmission by regulating the balance between SSC self-renewal and differentiation, and competitive spermatogonial transplantation technique will be useful for analyzing subtle defects in spermatogenesis that are not evident by traditional spermatogonial transplantation.
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