Sirt1 deficiency attenuates spermatogenesis and germ cell function.
Sirt1 deficiency attenuates spermatogenesis and germ cell function.
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SIRT1缺乏会减弱精子发生和生殖细胞功能。
DOI：
10.1371/journal.pone.0001571
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发表时间：
2008-02-13
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
在哺乳动物中，Sirt1是sirtuin蛋白家族的一员，作为烟酰胺腺嘌呤二核苷酸依赖的蛋白去乙酰化酶，具有重要的生理作用，包括调节葡萄糖代谢、细胞存活和线粒体呼吸。对Sirt1缺陷小鼠的初步研究揭示了一种包括寿命缩短、体积小和异常精子频率增加的表型。我们现在对Sirt1敲除（- / -）小鼠种系中Sirt1缺乏的分子和功能影响进行了详细分析。我们发现Sirt1缺乏明显减弱精子的发生，而不是卵子的发生。Sirt1−/−小鼠的成熟精子和生精前体的数量，早在发育的第15.5天就显著减少（减少了2-10倍；P≤0.004），而Sirt1缺乏并不影响雌性小鼠超排卵后卵母细胞产生的效率。此外，成熟精子中DNA损伤升高的比例（约占总附睾精子的7.5%,P = 0.02）在成年Sirt1−/−雄性中显著增加。通过基因芯片分析Sirt1缺陷睾丸的整体基因表达，发现85个基因表达异常，其中与精子发生和蛋白质聚合相关的基因表达异常（P<0.05）。为了评估Sirt1缺陷生殖细胞的功能，我们在体外受精（IVF）实验中比较了来自Sirt1−/−和同胞Sirt1+/−小鼠的配子产生胚胎和可存活后代的效率。虽然Sirt1 - / - X野生型和Sirt1 - / - X Sirt1 - / -杂交均可获得活的动物，但当使用Sirt1 - / -精子和/或卵母细胞进行体外受精时，产生2细胞受精卵和活的后代的效率降低。总之，这些数据支持Sirt1在精子发生，包括生精干细胞，以及生殖细胞功能中的重要作用。
In mammals, Sirt1, a member of the sirtuin family of proteins, functions as a nicotinamide adenine dinucleotide-dependent protein deactylase, and has important physiological roles, including the regulation of glucose metabolism, cell survival, and mitochondrial respiration. The initial investigations of Sirt1 deficient mice have revealed a phenotype that includes a reduced lifespan, small size, and an increased frequency of abnormal sperm. We have now performed a detailed analysis of the molecular and functional effects of Sirt1 deficiency in the germ line of Sirt1 knock-out (−/−) mice. We find that Sirt1 deficiency markedly attenuates spermatogenesis, but not oogenesis. Numbers of mature sperm and spermatogenic precursors, as early as d15.5 of development, are significantly reduced (∼2-10-fold less; P≤0.004) in numbers in Sirt1−/− mice, whereas Sirt1 deficiency did not effect the efficiency oocyte production following superovulation of female mice. Furthermore, the proportion of mature sperm with elevated DNA damage (∼7.5% of total epididymal sperm; P = 0.02) was significantly increased in adult Sirt1−/− males. Analysis of global gene expression by microarray analysis in Sirt1 deficient testis revealed dysregulated expression of 85 genes, which were enriched (P<0.05) for genes involved in spermatogenesis and protein sumoylation. To assess the function of Sirt1 deficient germ cells, we compared the efficiency of generating embryos and viable offspring in in vitro fertilization (IVF) experiments using gametes from Sirt1−/− and sibling Sirt1+/− mice. While viable animals were derived in both Sirt1−/− X wild type and Sirt1−/− X Sirt1−/− crosses, the efficiency of producing both 2-cell zygotes and viable offspring was diminished when IVF was performed with Sirt1−/− sperm and/or oocytes. Together, these data support an important role for Sirt1 in spermatogenesis, including spermatogenic stem cells, as well as germ cell function.
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影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
9.8
作者：
Bordone L;Motta MC;Picard F;Robinson A;Jhala US;Apfeld J;McDonagh T;Lemieux M;McBurney M;Szilvasi A;Easlon EJ;Lin SJ;Guarente L
通讯作者：
Guarente L
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P
影响因子：
3.6
作者：
Coussens, Matthew;Yamazaki, Yukiko;Allsopp, Richard
通讯作者：
Allsopp, Richard
影响因子：
10.5
作者：
BRACHMANN, CB;SHERMAN, JM;BOEKE, JD
通讯作者：
BOEKE, JD