Adjudin disrupts spermatogenesis via the action of some unlikely partners
Adjudin disrupts spermatogenesis via the action of some unlikely partners
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DOI：
10.4161/spmg.1.4.18393
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发表时间：
2011-10
期刊：
影响因子：
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通讯作者：
Yan-ho Cheng;C. Cheng;Pearl P Y Lie;Elissa W P Wong;D. Mruk;B. Silvestrini
中科院分区：
文献类型：
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作者：
Yan-ho Cheng;C. Cheng;Pearl P Y Lie;Elissa W P Wong;D. Mruk;B. Silvestrini
Adjudin，1-（2，4-二氯苄基）-1H-吲唑-3-碳酰肼（以前称为AF-2364），是氯尼达明[1-（2，4-二氯苄基）-1H-吲唑-3-羧酸]的有效类似物，已知可破坏成年大鼠睾丸生精上皮中的生殖细胞粘附，最显著的是延长和拉长精子细胞，因此导致大鼠不育。由于生精小管中精原细胞和精原干细胞（SSC）的数量没有显著减少与adjudin治疗大鼠，adjudin诱导的不孕症是高度可逆的使用适当的方案，这使得重新启动精子发生和生殖细胞重新种群的空洞生精上皮。此外，adjudin似乎发挥其作用，在睾丸特异性的非典型粘附连接（AJ）类型被称为外质特化（ES），最显着的顶端ES在支持细胞精子细胞界面。因此，下丘脑-垂体-性腺轴不受影响，全身副作用极小。这也使得adjudin成为男性避孕药开发的潜在候选者。在此，我们批判性地评估了该领域的最新研究结果，并提供了一个更新的模型，关于调整诱导的顶端ES中断的机制。简而言之，通过抑制Eps 8（表皮生长因子受体途径底物8）（一种在肌动蛋白成束中也起作用的肌动蛋白加帽蛋白）的表达，调节素靶向顶端ES处的肌动蛋白丝束，这是在哺乳动物的任何其他上皮/内皮中未发现的睾丸特异性连接类型的标志，使得肌动蛋白丝束不再能够维持在顶端ES处。这是伴随着Arp 3（肌动蛋白相关蛋白3，Arp 2/3复合物的一种成分，诱导肌动蛋白成核/分支）的错误定位，导致“不必要的”肌动蛋白分支，进一步破坏肌动蛋白丝束在顶端ES。此外，调节素阻断PAR 6（分配缺陷蛋白6）和14-3-3（也称为PAR 5）在顶端ES的表达，破坏内吞囊泡介导的蛋白质运输的稳态，这反过来导致蛋白质内吞作用的增加。这些变化的净结果使细胞粘附不稳定，并诱导顶端ES变性，导致精子细胞过早释放，模仿精子形成。
Adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (formerly called AF-2364), is a potent analog of lonidamine [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] known to disrupt germ cell adhesion, most notably elongating and elongated spermatids, in the seminiferous epithelium of adult rat testes and thus, leads to infertility in rats. Since the population of spermatogonia and spermatogonial stem cells (SSCs) in the seminiferous tubules is not significantly reduced by the treatment of rats with adjudin, adjudin-induced infertility is highly reversible with the use of appropriate regimens, which enables re-initiation of spermatogenesis and germ cell re-population of the voided seminiferous epithelium. Furthermore, adjudin appears to exert its effects at the testis-specific atypical adherens junction (AJ) type known as ectoplasmic specialization (ES), most notably the apical ES at the Sertoli cell-spermatid interface. Thus, the hypothalamic-pituitary-gonadal axis is not unaffected and systemic side-effects are minimal. This also makes adjudin a potential candidate for male contraceptive development. Herein, we critically evaluate recent findings in the field and provide an updated model regarding the mechanism underlying adjudin-induced apical ES disruption. In short, adjudin targets actin filament bundles at the apical ES, the hallmark of this testis-specific junction type not found in any other epithelia/endothelia in mammals, by suppressing the expression of Eps8 (epidermal growth factor receptor pathway substrate 8), an actin capping protein that also plays a role in actin bundling, so that actin filament bundles can no longer be maintained at the apical ES. This is concomitant with a mis-localization of Arp3 (actin-related protein 3, a component of the Arp2/3 complex that induces actin nucleation/branching), causing “unwanted” actin branching, further destabilizing actin filament bundles at the apical ES. Additionally, adjudin blocks the expression of PAR6 (partitioning defective protein 6) and 14–3-3 (also known as PAR5) considerably at the apical ES, disrupting the homeostasis of endocytic vesicle-mediated protein trafficking, which in turn leads to an increase in protein endocytosis. The net result of these changes destabilizes cell adhesion and induces degeneration of the apical ES, causing premature release of spermatids, mimicking spermiation.