The alteration of RhoA geranylgeranylation and Ras farnesylation breaks the integrity of the blood–testis barrier and results in hypospermatogenesis
The alteration of RhoA geranylgeranylation and Ras farnesylation breaks the integrity of the blood–testis barrier and results in hypospermatogenesis
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RhoA 香叶基香叶基化和 Ras 法呢基化的改变破坏了血睾屏障的完整性，导致精子生成不足
DOI：
10.1038/s41419-019-1688-9
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发表时间：
2019
影响因子：
9
通讯作者：
Chaojun Li
中科院分区：
文献类型：
--
作者：
Ruilou Zhu;Jiangnan Wang;Tianxiang Feng;Xuechun Hu;Chen Jiang;Xiuxing Wang;Kang Li;Yongjuan Sang;Yue Hua;Haixiang Sun;Bing Yao;Chaojun Li
非阻塞性无精子症（NOA）严重影响男性不育，然而，这种疾病的深层机制很少被解释。在本研究中，我们发现未分化的精原干细胞（SSCs）仍然存在于精小管基底室中，并且在NOA生精成熟阻滞患者中，邻近的支持细胞（SCs）相互作用形成的血睾丸屏障（BTB）是不完整的。在NOA患者中，SCs和生殖细胞（GCs）之间的粘附也被破坏。同时，甲羟戊酸代谢途径的关键酶——香叶二磷酸合成酶（Ggpps）在NOA患者中的表达水平低于阻塞性无精子症（OA）患者。在sc中特异性地缺失ggpps后，小鼠不育，SC-Ggpps−/−小鼠的表型与NOA患者相似，BTB和SC-GC粘连被严重破坏。尽管SC-Ggpps - / -小鼠精管基底室中仍有ssc，但成熟精母细胞和精母细胞较少。进一步的研究表明，该缺陷是由ggpps缺失后RhoA和Ras家族的异常蛋白异戊二烯化介导的。令人兴奋的发现是，当给敲除小鼠注射小檗碱时，异常的细胞粘连得到改善，精子发生得到部分恢复。我们的数据表明，重建中断的BTB是NOA患者生精成熟阻滞和精子发生不足的有效治疗策略。
Non-obstructive azoospermia (NOA) severely affects male infertility, however, the deep mechanisms of this disease are rarely interpreted. In this study, we find that undifferentiated spermatogonial stem cells (SSCs) still exist in the basal compartment of the seminiferous tubules and the blood–testis barrier (BTB) formed by the interaction of neighbor Sertoli cells (SCs) is incomplete in NOA patients with spermatogenic maturation arrest. The adhesions between SCs and germ cells (GCs) are also broken in NOA patients. Meanwhile, the expression level of geranylgeranyl diphosphate synthase (Ggpps), a key enzyme in mevalonate metabolic pathway, is lower in NOA patients than that in obstructive azoospermia (OA) patients. AfterGgppsdeletion specifically in SCs, the mice are infertile and the phenotype of the SC-Ggpps−/−mice is similar to the NOA patients, where the BTB and the SC–GC adhesions are severely destroyed. Although SSCs are still found in the basal compartment of the seminiferous tubules, fewer mature spermatocyte and spermatid are found in SC-Ggpps−/−mice. Further examination suggests that the defect is mediated by the aberrant protein isoprenylation of RhoA and Ras family afterGgppsdeletion. The exciting finding is that when the knockout mice are injected with berberine, the abnormal cell adhesions are ameliorated and spermatogenesis is partially restored. Our data suggest that the reconstruction of disrupted BTB is an effective treatment strategy for NOA patients with spermatogenic maturation arrest and hypospermatogenesis.