Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice.
Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice.
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DOI：
10.1371/journal.pgen.1000199
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发表时间：
2008-09-19
期刊：
影响因子：
4.5
通讯作者：
Adams IR
中科院分区：
文献类型：
--
作者：
Ollinger R;Childs AJ;Burgess HM;Speed RM;Lundegaard PR;Reynolds N;Gray NK;Cooke HJ;Adams IR
由于遗传信息是通过连续几代传递的，它在早期胚胎的多能细胞和发育中的胎儿和成年动物的生殖细胞之间传递。Tex19.1编码一种功能未知的蛋白质，其表达仅限于生殖细胞和多能细胞。在雄性精子发生过程中，Tex19.1在有丝分裂的精原细胞中表达最高，并随着这些细胞的分化和减数分裂的进展而减少。在多能干细胞中，Tex19.1表达在分化时也下调。然而，目前尚不清楚Tex19.1是否在生殖细胞或多能干细胞中具有重要功能，或者这种功能可能是什么。为了分析Tex19.1在多能性或生殖细胞功能中的潜在作用，我们产生了Tex19.1−/−敲除小鼠并分析了Tex19.1−/−突变表型。成年Tex19.1−/−基因敲除雄性表现出精子发生受损。免疫组化和组织学分析显示减数分裂染色体联会缺陷，减数分裂过程中DNA双链断裂的持久性，以及减数分裂后睾丸生殖细胞的损失。此外，一类内源性逆转录病毒的表达在Tex19.1−/−睾丸减数分裂期间上调。Tex19.1−/−突变小鼠生殖系中内源性逆转录病毒转座的增加，以及随之而来的DNA损伤的增加，可能足以破坏减数分裂期间重组和染色体突触的正常过程，并导致精子发生缺陷。我们的研究结果表明，Tex19.1是一个专门的机制，在生殖细胞抑制转座遗传因子，并通过连续几代保持基因组的稳定性的一部分。生殖细胞雌性的卵子和雄性的精子负责将遗传信息从一代传递到下一代。由于生殖细胞中出现的任何遗传变化都可以传递给下一代，因此生殖细胞是移动的遗传元件活动的主要目标。移动的遗传元件约占哺乳动物基因组的40%，并且这些元件中的许多来自感染生殖细胞或生殖细胞的早期胚胎前体的逆转录病毒，并且已经整合到基因组中。在这里，我们研究了Tex19.1的功能，Tex19.1是一种基因，其表达仅限于生殖细胞和多能细胞，这些细胞是生殖细胞的早期胚胎前体。我们发现，当Tex19.1从小鼠中删除时，生殖细胞在减数分裂过程中出现问题，精子产生受损。此外，我们发现，在没有Tex19.1的情况下，内源性逆转录病毒在试图通过减数分裂的雄性生殖细胞中被激活。我们的研究结果表明，Tex19.1是一个专门的机制，防止在生殖细胞和多能细胞的诱变内源性逆转录病毒活性的一部分，从而有助于保持基因组的完整性和稳定性，通过连续几代。
As genetic information is transmitted through successive generations, it passes between pluripotent cells in the early embryo and germ cells in the developing foetus and adult animal. Tex19.1 encodes a protein of unknown function, whose expression is restricted to germ cells and pluripotent cells. During male spermatogenesis, Tex19.1 expression is highest in mitotic spermatogonia and diminishes as these cells differentiate and progress through meiosis. In pluripotent stem cells, Tex19.1 expression is also downregulated upon differentiation. However, it is not clear whether Tex19.1 has an essential function in germ cells or pluripotent stem cells, or what that function might be. To analyse the potential role of Tex19.1 in pluripotency or germ cell function we have generated Tex19.1−/− knockout mice and analysed the Tex19.1−/− mutant phenotype. Adult Tex19.1−/− knockout males exhibit impaired spermatogenesis. Immunostaining and histological analysis revealed defects in meiotic chromosome synapsis, the persistence of DNA double-strand breaks during meiosis, and a loss of post-meiotic germ cells in the testis. Furthermore, expression of a class of endogenous retroviruses is upregulated during meiosis in the Tex19.1−/− testes. Increased transposition of endogenous retroviruses in the germline of Tex19.1−/− mutant mice, and the concomitant increase in DNA damage, may be sufficient to disrupt the normal processes of recombination and chromosome synapsis during meiosis and cause defects in spermatogenesis. Our results suggest that Tex19.1 is part of a specialised mechanism that operates in the germline to repress transposable genetic elements and maintain genomic stability through successive generations. The germ cells—eggs in females and sperm in males—are responsible for passing genetic information from one generation to the next. As any genetic changes that arise in the germ cells can be transmitted to the next generation, germ cells are a prime target for the activity of mobile genetic elements. Mobile genetic elements make up around 40% of a mammalian genome, and many of these elements are derived from retroviruses that have infected germ cells, or early embryonic precursors to germ cells, and have integrated into the genome. Here, we characterise the function of Tex19.1, a gene whose expression is restricted to germ cells and the pluripotent cells that are early embryonic precursors to germ cells. We show that when Tex19.1 is deleted from mice, germ cells have problems progressing through meiosis, and sperm production is impaired. Furthermore, we show that, in the absence of Tex19.1, endogenous retroviruses are activated in male germ cells attempting to go through meiosis. Our results suggest that Tex19.1 is part of a specialised mechanism that guards against mutagenic endogenous retrovirus activity in germ cells and pluripotent cells and thus helps to maintain the integrity and stability of the genome through successive generations.
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