Transmission distortion by loss of p21 or p27 cyclin-dependent kinase inhibitors following competitive spermatogonial transplantation

被引:33
作者
Kanatsu-Shinohara, Mito [1 ]
Takashima, Seiji [1 ]
Shinohara, Takashi [1 ,2 ]
机构
[1] Kyoto Univ, Grad Sch Med, Dept Mol Genet, Kyoto 6068501, Japan
[2] Japan Sci & Technol Agcy, Kyoto 6068501, Japan
基金
日本科学技术振兴机构;
关键词
germline transmission; spermatogenesis; stem cell; cyclin-dependent kinase inhibitor; self-renewal; CELL SELF-RENEWAL; UNDIFFERENTIATED SPERMATOGONIA; STEM-CELLS; CLONAL ORIGIN; PROLIFERATION; P27(KIP1); MICE; ACTIVATION; CAPACITY; ARREST;
D O I
10.1073/pnas.0914448107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:6210 / 6215
页数:6
相关论文
共 29 条
  • [11] Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine sertoli cell proliferation
    Holsberger, DR
    Buchold, GM
    Leal, MC
    Kiesewetter, SE
    O'Brien, DA
    Hess, RA
    França, LR
    Kiyokawa, H
    Cooke, PS
    [J]. BIOLOGY OF REPRODUCTION, 2005, 72 (06) : 1429 - 1436
  • [12] Long-term proliferation in culture and germline transmission of mouse male germline stem cells
    Kanatsu-Shinohara, M
    Ogonuki, N
    Inoue, K
    Miki, H
    Ogura, A
    Toyokuni, S
    Shinohara, T
    [J]. BIOLOGY OF REPRODUCTION, 2003, 69 (02) : 612 - 616
  • [13] Clonal origin of germ cell colonies after spermatogonial transplantation in mice
    Kanatsu-Shinohara, Mito
    Inoue, Kimiko
    Miki, Hiromi
    Ogonuki, Narumi
    Takehashi, Masanori
    Morimoto, Takeshi
    Ogura, Atsuo
    Shinohara, Takashi
    [J]. BIOLOGY OF REPRODUCTION, 2006, 75 (01) : 68 - 74
  • [14] P21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity
    Kippin, TE
    Martens, DJ
    van der Kooy, D
    [J]. GENES & DEVELOPMENT, 2005, 19 (06) : 756 - 767
  • [15] Genetic Reconstruction of Mouse Spermatogonial Stem Cell Self-Renewal In Vitro by Ras-Cyclin D2 Activation
    Lee, Jiyoung
    Kanatsu-Shinohara, Mito
    Morimoto, Hiroko
    Kazuki, Yasuhiro
    Takashima, Seiji
    Oshimura, Mitsuo
    Toyokuni, Shinya
    Shinohara, Takashi
    [J]. CELL STEM CELL, 2009, 5 (01) : 76 - 86
  • [16] Increased Proliferation but Decreased Steroidogenic Capacity in Leydig Cells from Mice Lacking Cyclin-Dependent Kinase Inhibitor 1B
    Lin, Han
    Hu, Guo-Xin
    Dong, Lei
    Dong, Qiang
    Mukai, Motoko
    Chen, Bing-Bing
    Holsberger, Denise R.
    Sottas, Chantal M.
    Cooke, Paul S.
    Lian, Qing-Quan
    Li, Xiao-Kun
    Ge, Ren-Shan
    [J]. BIOLOGY OF REPRODUCTION, 2009, 80 (06) : 1232 - 1238
  • [17] Meistrich ML., 1993, CELL MOL BIOL TESTIS, P266
  • [18] Regulation of cell fate decision of undifferentiated spermatogonia by GDNF
    Meng, XJ
    Lindahl, M
    Hyvönen, ME
    Parvinen, M
    de Rooij, DG
    Hess, MW
    Raatikainen-Ahokas, A
    Sainio, K
    Rauvala, H
    Lakso, M
    Pichel, JG
    Westphal, H
    Saarma, M
    Sariola, H
    [J]. SCIENCE, 2000, 287 (5457) : 1489 - 1493
  • [19] Pattern and kinetics of mouse donor spermatogonial stem cell colonization in recipient testes
    Nagano, M
    Avarbock, MR
    Brinster, RL
    [J]. BIOLOGY OF REPRODUCTION, 1999, 60 (06) : 1429 - 1436
  • [20] Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors
    Nakayama, K
    Ishida, N
    Shirane, M
    Inomata, A
    Inoue, T
    Shishido, N
    Hori, I
    Loh, DY
    Nakayama, K
    [J]. CELL, 1996, 85 (05) : 707 - 720