Regulation of the blood-testis barrier by a local axis in the testis: role of laminin 2 in the basement membrane
Regulation of the blood-testis barrier by a local axis in the testis: role of laminin 2 in the basement membrane
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DOI：
10.1096/fj.201600870r
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发表时间：
2017-02-01
期刊：
影响因子：
4.8
通讯作者：
Cheng, C. Yan
中科院分区：
文献类型：
--
作者：
Gao, Ying;Mruk, Dolores;Cheng, C. Yan
层粘连蛋白 2 是成年大鼠睾丸基底膜 (BM) 的组成成分之一。早期使用小鼠遗传模型的研究表明，层粘连蛋白 2 的缺失会破坏睾丸中支持细胞长度方向的外质特化（ES；睾丸特异性、富含肌动蛋白的锚定连接）功能，从而阻碍雄性生育能力。这包括支持细胞-伸长/伸长精子细胞界面处的 ES，称为顶端 ES，也可能包括血睾屏障 (BTB) 处的支持细胞-支持细胞界面，称为基底 ES。研究还表明，存在一个局部调节轴，在功能上将发生在顶端 ES 的小管管腔边缘附近的精子形成细胞事件与上皮周期期间生精上皮相对两端的 BM 附近的基底 ES/BTB 重塑联系起来，称为顶端 ES-BTB-BM 轴。然而，BM 在该轴中的确切作用仍然未知。在这里，我们发现 BM 中的层粘连蛋白 2 是该轴的关键调节因子，因为层粘连蛋白 2（可能是来自 C 末端的 80 kDa 片段）被发现在上皮周期的 VIII-IX 阶段穿过生精上皮，从 BM 运输到小管的管腔边缘，可能用于在这些阶段调节顶端 ES 重组。更重要的是，支持细胞中层粘连蛋白 2 的敲除可通过改变支持细胞 BTB 中紧密连接处的粘附蛋白和基底 ES 的定位来诱导支持细胞紧密连接通透性屏障破坏。发现这些变化是由肌动蛋白结合/调节蛋白的时空表达变化引起的 F-肌动蛋白组织破坏介导的。此外，敲低层粘连蛋白 2 还通过改变 EB1（末端结合蛋白 1）（一种 +TIP（MT 加末端跟踪蛋白））的时空表达，显着下调 MT 聚合，从而扰乱微管（MT）组织。简而言之，BM 中的层粘连蛋白 2 似乎通过调节精子发生过程中的 BTB 动力学，在 BTB-BM 轴中发挥着至关重要的作用。
Laminin 2 is one of the constituent components of the basement membrane (BM) in adult rat testes. Earlier studies that used a mouse genetic model have shown that a deletion of laminin 2 impedes male fertility by disrupting ectoplasmic specialization (ES; a testis-specific, actin-rich anchoring junction) function along the length of Sertoli cell in the testis. This includes ES at the Sertoli cell-elongating/elongated spermatid interface, which is known as apical ES and possibly the Sertoli-Sertoli cell interface, known as basal ES, at the blood-testis barrier (BTB). Studies have also illustrated that there is a local regulatory axis that functionally links cellular events of spermiation that occur near the luminal edge of tubule lumen at the apical ES and the basal ES/BTB remodeling near the BM at opposite ends of the seminiferous epithelium during the epithelial cycle, known as the apical ES-BTB-BM axis. However, the precise role of BM in this axis remains unknown. Here, we show that laminin 2 in the BM serves as the crucial regulator in this axis as laminin 2, likely its 80-kDa fragment from the C terminus, was found to be transported across the seminiferous epithelium at stages VIII-IX of the epithelial cycle, from the BM to the luminal edge of the tubule, possibly being used to modulate apical ES restructuring at these stages. Of more importance, a knockdown of laminin 2 in Sertoli cells was shown to induce the Sertoli cell tight junction permeability barrier disruption via changes in localization of adhesion proteins at the tight junction and basal ES at the Sertoli cell BTB. These changes were found to be mediated by a disruption of F-actin organization that was induced by changes in the spatiotemporal expression of actin binding/regulatory proteins. Furthermore, laminin 2 knockdown also perturbed microtubule (MT) organization by considerable down-regulation of MT polymerization via changes in the spatiotemporal expression of EB1 (end-binding protein 1), a +TIP (MT plus-end tracking protein). In short, laminin 2 in the BM seems to play a crucial role in the BTB-BM axis by modulating BTB dynamics during spermatogenesis.