Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice.
Alteration of protein prenylation promotes spermatogonial differentiation and exhausts spermatogonial stem cells in newborn mice.
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蛋白质异戊二烯化的改变促进新生小鼠精原细胞分化并耗尽精原干细胞
DOI：
10.1038/srep28917
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发表时间：
2016-07-04
影响因子：
4.6
通讯作者：
Li CJ
中科院分区：
文献类型：
--
作者：
Diao F;Jiang C;Wang XX;Zhu RL;Wang Q;Yao B;Li CJ
成年期的精子发生依赖于精原干细胞库在新生儿期的成功建立和青春期的逐渐分化。生精上皮中蛋白质异戊二烯化的阶段依赖性变化可能在性成熟前的第一轮精子发生中起重要作用，但其机制尚不清楚。我们以前发现，在新生儿睾丸中，支持细胞的异戊烯化改变可诱导精原细胞凋亡，从而导致成人不育。本研究利用在胚胎期和减数分裂后期条件性缺失香叶基香叶基二磷酸合酶（Ggpps）的方法，进一步探讨了蛋白质异戊二烯化在生殖细胞中的作用。我们观察到Ggpps−/− Ddx 4-Cre小鼠的不育症，这些小鼠表现出仅支持细胞综合征的表型，这是由青春期前阶段的异常精原细胞分化和SSC耗竭引起的。形态学特征和细胞特异性标记物分析表明，精原细胞分化早在生后第7天的第一轮精子发生中就开始增强。分子机制的研究表明，Ggpps缺失增强Rheb法尼基化，随后激活mTORC 1，促进精原细胞分化。总之，在生殖细胞中的异戊二烯化平衡是至关重要的精原细胞分化的命运决定在青春期前阶段，这一进程的中断导致原发性不育。
Spermatogenesis in adulthood depends on the successful neonatal establishment of the spermatogonial stem cell (SSC) pool and gradual differentiation during puberty. The stage-dependent changes in protein prenylation in the seminiferous epithelium might be important during the first round of spermatogenesis before sexual maturation, but the mechanisms are unclear. We have previous found that altered prenylation in Sertoli cells induced spermatogonial apoptosis in the neonatal testis, resulting in adult infertility. Now we further explored the role of protein prenylation in germ cells, using a conditional deletion of geranylgeranyl diphosphate synthase (Ggpps) in embryonic stage and postmeiotic stage respectively. We observed infertility of Ggpps−/− Ddx4-Cre mice that displayed a Sertoli-cell-only syndrome phenotype, which resulted from abnormal spermatogonial differentiation and SSC depletion during the prepubertal stage. Analysis of morphological characteristics and cell-specific markers revealed that spermatogonial differentiation was enhanced from as early as the 7th postnatal day in the first round of spermatogenesis. Studies of the molecular mechanisms indicated that Ggpps deletion enhanced Rheb farnesylation, which subsequently activated mTORC1 and facilitated spermatogonial differentiation. In conclusion, the prenylation balance in germ cells is crucial for spermatogonial differentiation fate decision during the prepubertal stage, and the disruption of this process results in primary infertility.