Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine sertoli cell proliferation
Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine sertoli cell proliferation
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DOI：
10.1095/biolreprod.105.040386
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发表时间：
2005-06-01
影响因子：
3.6
通讯作者：
Cooke, PS
中科院分区：
文献类型：
--
作者：
Holsberger, DR;Buchold, GM;Cooke, PS
甲状腺激素抑制新生儿支持细胞增殖，最近的结果表明，甲状腺激素上调新生儿支持细胞中的细胞周期蛋白依赖性激酶抑制剂（CDKIs）p27（Kip 1）和p21（Cip 1）（也分别称为CDKN 1B和CDKN 1A）。这表明这些负调节细胞周期的CDK 1在支持细胞增殖中可能是关键的。与这一假设相一致，缺乏p27（Kip 1）的小鼠发展为睾丸器官肿大，但支持细胞数量尚未确定。同样，p21（Cip 1）或p27和p21缺失对支持细胞数量和睾丸发育的影响也未知。为了确定p27和/或p21是否调节支持细胞增殖，我们测量了4月龄野生型（WT）、p21敲除（p21 KO）、p27敲除（p27 KO）和p27/p21双敲除（DBKO）小鼠出生后第16天的支持细胞增殖和睾丸重量、支持细胞数量和每日精子产量（DSP）。与WT相比，成年p21 KO、p27 KO和DBKO小鼠的睾丸重量分别增加了27%、42%和86%。与WT相比，p21 KO、p27 KO和DBKO小鼠的支持细胞数量也分别增加了48%、126%和126%。与WT小鼠相比，p21 KO、p27 KO和DBKO睾丸中的DSP也显示出显著增加。尽管DSP增加，但与WT相比，在p27 KO和DBKO小鼠中观察到的生精缺陷增加。这些数据表明，p27和p21在调节成人支持细胞数量中起抑制作用，使得CDKI的损失产生支持细胞数量的初级增加和DSP和睾丸重量的次级增加。此外，这两个CDKI的损失导致DSP和睾丸重量的叠加效应，表明这些CDKI在睾丸发育中的核心作用。
Thyroid hormone inhibits neonatal Sertoli cell proliferation and recent results have shown that thyroid hormone upregulates cyclin-dependent kinase inhibitors (CDKIs) p27(Kip1) and p21(Cip1) (also known as CDKN1B and CDKN1A, respectively) in neonatal Sertoli cells. This suggests that these CDKls, which negatively regulate the cell cycle, could be critical in Sertoli cell proliferation. Consistent with this hypothesis, mice lacking p27(Kip1) develop testicular organomegaly, but Sertoli cell numbers have not been determined. Likewise, effects of loss of p21(Cip1) or both p27 and p21 on Sertoli cell number and testicular development were unknown. To determine if p27 and/or p21 regulate Sertoli cell proliferation, we measured Sertoli cell proliferation at Postnatal Day 16 and testis weight, Sertoli cell number, and daily sperm production (DSP) in 4-mo-old wild-type (WT), p21 knockout (p21KO), p27 knockout (p27KO), and p27/p21 double-knockout (DBKO) mice. Testis weights were increased 27%, 42%, and 86% in adult p21KO, p27KO, and DBKO mice, respectively, compared with WT. Sertoli cell number also was increased 48%, 126%, and 126% in p21KO, p27KO, and DBKO mice, respectively, versus WT. DSP in p21KO, p27KO, and DBKO testes also showed significant increases compared with WT mice. Although DSP was increased, there were increased spermatogenic defects observed in both p27KO and DBKO mice compared with WT. These data indicate that both p27 and p21 play an inhibitory role in regulating adult Sertoli cell number such that loss of either CDKI produces primary increases in Sertoli cell number and secondary increases in DSP and testis weight. Furthermore, loss of both CDKIs causes additive effects on DSP and testis weight, suggesting a central role for these CDKIs in testis development.