Impaired germ cell development due to compromised cell cycle progression in Skp2-deficient mice
Impaired germ cell development due to compromised cell cycle progression in Skp2-deficient mice
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DOI：
10.1186/1747-1028-1-4
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发表时间：
2006-01-01
期刊：
影响因子：
2.3
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Fotovati, Abbas;Nakayama, Keiko;Nakayama, Keiichi I.
背景：生殖腺通过有丝分裂和减数分裂产生生殖细胞。Skp 2是SCF型泛素连接酶的受体亚基，是细胞进入细胞周期S期的主要调节因子，它通过介导细胞增殖抑制剂p27的泛素依赖性降解来促进细胞进入S期。然而，Skp 2-p27通路在生殖细胞development.Results中的作用仍然难以捉摸：我们现在表明，Skp 2在小鼠中的破坏导致男性生育能力的显着损害，与男性支持细胞综合征的表型相似。Skp 2（-/-）小鼠睾丸表现出明显的生殖细胞发育不全，伴随着大量的生精细胞凋亡。流式细胞术显示，精子多倍体的患病率增加，这表明这些细胞的非整倍性是负责诱导细胞凋亡。破坏的p27基因的Skp 2（-/-）小鼠恢复生殖细胞的发育，表明睾丸发育不良的Skp 2（-/-）动物是由于p27 accumulation.Conclusion的抗增殖作用：因此，我们的研究结果表明，受损的细胞周期进程所造成的积累的p27的结果在非整倍体和诱导凋亡的Skp 2（-/-）小鼠的性腺细胞。结果是成熟配子数量减少，这是这些动物生育力下降的原因。这些发现加强了Skp 2-p27通路在细胞周期调控和生殖细胞发育中的重要性。
Background: The gonads are responsible for the production of germ cells through both mitosis and meiosis. Skp2 is the receptor subunit of an SCF-type ubiquitin ligase and is a major regulator of the progression of cells into S phase of the cell cycle, which it promotes by mediating the ubiquitin-dependent degradation of p27, an inhibitor of cell proliferation. However, the role of the Skp2-p27 pathway in germ cell development remains elusive.Results: We now show that disruption of Skp2 in mice results in a marked impairment in the fertility of males, with the phenotypes resembling Sertoli cell-only syndrome in men. Testes of Skp2(-/-) mice manifested pronounced germ cell hypoplasia accompanied by massive apoptosis in spermatogenic cells. Flow cytometry revealed an increased prevalence of polyploidy in spermatozoa, suggesting that the aneuploidy of these cells is responsible for the induction of apoptosis. Disruption of the p27 gene of Skp2(-/-) mice restored germ cell development, indicating that the testicular hypoplasia of Skp2(-/-) animals is attributable to the antiproliferative effect of p27 accumulation.Conclusion: Our results thus suggest that compromised cell cycle progression caused by the accumulation of p27 results in aneuploidy and the induction of apoptosis in gonadal cells of Skp2(-/-) mice. The consequent reduction in the number of mature gametes accounts for the decreased fertility of these animals. These findings reinforce the importance of the Skp2-p27 pathway in cell cycle regulation and in germ cell development.