Loss of Fbxw7 in Sertoli cells impairs testis development and causes infertility in mice
Loss of Fbxw7 in Sertoli cells impairs testis development and causes infertility in mice
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支持细胞中 Fbxw7 的缺失会损害睾丸发育并导致小鼠不育
DOI：
10.1093/biolre/ioz230
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发表时间：
2020
影响因子：
3.6
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Zhang H;Chen F;Dong H;Xie M;Zhang H;Chen Y;Liu H;Bai X;Li X;Chen Z
F-盒和WD-40结构域蛋白7(Fbxw7)是Skp1-CDC53/cullin-F-box-蛋白复合体(SCF/β-TrCP)的组成部分，是一种介导蛋白质降解的E3泛素连接酶。最近发现该复合体对精原干细胞的自我更新具有负性调节作用，但其在支持细胞(SC)增殖、分化和功能中的作用尚不清楚。在这项研究中，我们通过Cre-loxP系统获得了SC特异性缺失Fbxw7的条件突变小鼠。SCs缺乏Fbxw7会损害睾丸发育，其特征是年龄依赖性的小管萎缩、生殖细胞过度丧失和生精停止，突变的雄性在7个月大时就不育。Fbxw7去除也损害了SCs的细胞骨架组织和细胞极性，以及血-睾丸屏障的完整性。此外，在Fbxw7突变小鼠中，生殖细胞、间质细胞和干细胞的细胞标志物的转录水平显著降低。重要的是，在SC成熟和睾丸发育中起关键作用的转录因子GATA-4的蛋白水平在出生后14天后在对照SCs中逐渐降低，而在Fbxw7缺失的SCs中蛋白水平异常升高。有趣的是，在Fbxw7缺失后，GATA-4信使RNA水平保持稳定。干细胞中Fbxw7的沉默也导致进行性Leydig细胞效率低下和睾酮不足。总之，这些结果表明Fbxw7的表达是SC成熟和功能所必需的，可能是通过降解GATA-4来支持青春期睾丸发育和精子发生。
F-box and WD-40 domain protein 7 (Fbxw7) is a component of the Skp1-Cdc53/Cullin-F-box-protein complex (SCF/β-TrCP), which is an E3 ubiquitin ligase that mediates protein degradation. This complex has recently been shown to negatively regulate spermatogonial stem cell self-renewal; however, its roles in Sertoli cell (SC) proliferation, differentiation, and function remain to be established. In this study, we generated conditional mutant mice with SC-specific deletion ofFbxw7via the Cre-loxP system.Fbxw7deficiency in SCs impaired testis development, which is characterized by age-dependent tubular atrophy, excessive germ cell loss, and spermatogenic arrest, and the mutant males were infertile at 7 months old.Fbxw7ablation also compromised cytoskeletal organization and cell polarity of SCs, as well as integrity of the blood-testis barrier. In addition, the transcript levels of cell markers for germ cells, Leydig cells, and SCs were significantly decreased inFbxw7mutant mice. Importantly, protein levels of GATA-4, a transcription factor that plays a crucial role in SC maturation and testis development, were progressively decreased in control SCs after postnatal day 14, whereas levels were aberrantly elevated inFbxw7-deleted SCs. Interestingly, theGata-4messenger RNA levels remained stable followingFbxw7deletion.Fbxw7silencing in SCs also induced progressive Leydig cell inefficiency and testosterone insufficiency. Collectively, these results demonstrate that Fbxw7 expression is required for SC maturation and function, potentially through degradation of GATA-4, to support pubertal testis development and spermatogenesis.