Rictor Regulates Spermatogenesis by Controlling Sertoli Cell Cytoskeletal Organization and Cell Polarity in the Mouse Testis
Rictor Regulates Spermatogenesis by Controlling Sertoli Cell Cytoskeletal Organization and Cell Polarity in the Mouse Testis
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Rictor 通过控制小鼠睾丸中支持细胞的细胞骨架组织和细胞极性来调节精子发生
DOI：
10.1210/en.2015-1217
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发表时间：
2015-11-01
期刊：
影响因子：
4.8
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
--
作者：
Dong, Heling;Chen, Zhenguo;Bai, Xiaochun
维持细胞极性对于支持细胞和血睾屏障 (BTB) 功能以及精子发生至关重要；然而，调节细胞骨架完整性和支持细胞极性的信号传导机制尚不完全清楚。在这里，我们证明雷帕霉素靶点的雷帕霉素不敏感成分（TOR）（Rictor）是机械TOR复合物2（mTORC2）的核心成分，在睾丸发育过程中在生精上皮中表达，并在氯化镉诱导的BTB损伤模型中下调。然后，我们有条件地删除支持细胞中的 Rictor 基因，突变小鼠表现出无精子症，并且早在出生 3 个月时就处于不育状态。进一步的研究表明，Rictor 可能通过 mTORC2 依赖性和 mTORC2 独立机制来调节肌动蛋白组织，其中分别涉及小 GTP 酶、ras 相关的 C3 肉毒杆菌毒素底物 1 和肌动蛋白丝调节蛋白 Paxillin 的磷酸化。支持细胞中 Rictor 的缺失会扰乱肌动蛋白动力学并导致微管紊乱，这两者都会累积破坏支持细胞极性和 BTB 完整性，并伴有突变小鼠的睾丸发育缺陷、精子发生停滞和过度生殖细胞损失。总之，这些发现证实了 Rictor/mTORC2 信号传导通过维持支持细胞细胞骨架动力学、BTB 完整性和细胞极性在支持细胞功能和精子发生中的重要性。
Maintenance of cell polarity is essential for Sertoli cell and blood-testis barrier (BTB) function and spermatogenesis; however, the signaling mechanisms that regulate the integrity of the cytoskeleton and polarity of Sertoli cells are not fully understood. Here, we demonstrate that rapamycin-insensitive component of target of rapamycin (TOR) (Rictor), a core component of mechanistic TOR complex 2 (mTORC2), was expressed in the seminiferous epithelium during testicular development, and was down-regulated in a cadmium chloride-induced BTB damage model. We then conditionally deleted the Rictor gene in Sertoli cells and mutant mice exhibited azoospermia and were sterile as early as 3monthsold. Further study revealed that Rictor may regulate actin organization via both mTORC2-dependent and mTORC2-independent mechanisms, in which the small GTPase, ras-related C3 botulinum toxin substrate 1, and phosphorylation of the actin filament regulatory protein, Paxillin, are involved, respectively. Loss of Rictor in Sertoli cells perturbed actin dynamics and caused microtubule disarrangement, both of which accumulatively disrupted Sertoli cell polarity and BTB integrity, accompanied by testicular developmental defects, spermiogenic arrest and excessive germ cell loss in mutant mice. Together, these findings establish the importance of Rictor/mTORC2 signaling in Sertoli cell function and spermatogenesis through the maintenance of Sertoli cell cytoskeletal dynamics, BTB integrity, and cell polarity.