GASZ is essential for male meiosis and suppression of retrotransposon expression in the male germline.
GASZ is essential for male meiosis and suppression of retrotransposon expression in the male germline.
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DOI：
10.1371/journal.pgen.1000635
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Matzuk MM
中科院分区：
文献类型：
--
作者：
Ma L;Buchold GM;Greenbaum MP;Roy A;Burns KH;Zhu H;Han DY;Harris RA;Coarfa C;Gunaratne PH;Yan W;Matzuk MM
NuAGE是雄性生殖细胞胞浆中的无定形超微颗粒，与果蝇、非洲爪哇和智人一样分化。大多数Nuage是细胞质核糖核蛋白结构，参与多种RNA代谢，包括PIWI家族(即MILI、MIWI2和MIWI)对PIWI相互作用RNA(PiRNA)合成的调节。MILI主要存在于胚胎和出生后早期的生殖细胞中，也称为生发颗粒，常与线粒体和线粒体间粘连联系在一起。我们发现GASZ(带有Ankyrin重复序列的生殖细胞蛋白，不育的α基序和亮氨酸拉链)与Mili共定位在线粒体间粘连中。在小鼠中敲除GASZ导致MILI显著下调，并出现MILI缺失小鼠中观察到的合子线粗线型精母细胞障碍和男性不育缺陷。在GASZ缺失的睾丸中，我们观察到类似于MILI缺失的睾丸的低甲基化和反转录转座子的表达增加。我们还发现小RNAome中的全球变化，包括重复相关的、已知的和新的piRNAs的下调。这些研究首次证明了GASZ在男性生育和逆转座子的表观遗传和转录后沉默中发挥了重要的结构作用，稳定了NAGE中的Mili。RNA加工的许多方面对于生殖细胞的分化是必不可少的或突出的。动物生殖细胞中的一些RNA新陈代谢与围绕细胞核的物理结构有关，这种结构被称为Nuage。在减数分裂之前，Nuage具有明显的颗粒状外观，功能不明确。我们已经确定了一种名为GASZ的蛋白质，它在这种早期营养中发挥着结构性作用。在缺乏GASZ的小鼠中，反转录转座子-内源性病毒样颗粒-通过丢失称为piRNAs的小RNA而从生殖系中典型的抑制状态释放出来，导致DNA损伤和生殖细胞成熟延迟。为了保护生殖系免受遗传入侵者的侵袭，可能需要通过与GASZ直接或间接的联系，将piRNA合成酶和这种核糖体结构的其他成分联系起来。GASZ和其他营养素成分的突变可能导致不产生精子的男性不育。
Nuage are amorphous ultrastructural granules in the cytoplasm of male germ cells as divergent as Drosophila, Xenopus, and Homo sapiens. Most nuage are cytoplasmic ribonucleoprotein structures implicated in diverse RNA metabolism including the regulation of PIWI-interacting RNA (piRNA) synthesis by the PIWI family (i.e., MILI, MIWI2, and MIWI). MILI is prominent in embryonic and early post-natal germ cells in nuage also called germinal granules that are often associated with mitochondria and called intermitochondrial cement. We find that GASZ (Germ cell protein with Ankyrin repeats, Sterile alpha motif, and leucine Zipper) co-localizes with MILI in intermitochondrial cement. Knockout of Gasz in mice results in a dramatic downregulation of MILI, and phenocopies the zygotene–pachytene spermatocyte block and male sterility defect observed in MILI null mice. In Gasz null testes, we observe increased hypomethylation and expression of retrotransposons similar to MILI null testes. We also find global shifts in the small RNAome, including down-regulation of repeat-associated, known, and novel piRNAs. These studies provide the first evidence for an essential structural role for GASZ in male fertility and epigenetic and post-transcriptional silencing of retrotransposons by stabilizing MILI in nuage. Many aspects of RNA processing are essential for or prominent in the differentiation of germ cells. Some RNA metabolism in animal germ cells is associated with physical structures surrounding the cell nucleus called nuage. Nuage has a distinct granular appearance prior to the meiotic divisions with unclear functions. We have identified a protein called GASZ, which plays a structural role in this early nuage. In mice lacking GASZ, retrotransposons—endogenous viral-like particles—become released from their typical repressed state in the germline by the loss of small RNAs called piRNAs, resulting in DNA damage and delayed germ cell maturation. Protection of the germline from genetic intruders may require the association of piRNA-synthesizing enzymes and other components of this nuage structure through direct or indirect associations with GASZ. Mutations in GASZ and other nuage components may contribute to infertility in men who do not produce spermatozoa.
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影响因子：
1.7
作者：
Jurka, J;Kapitonov, VV;Walichiewicz, J
通讯作者：
Walichiewicz, J
影响因子：
10.5
作者：
Babiarz, Joshua E.;Ruby, J. Graham;Blelloch, Robert
通讯作者：
Blelloch, Robert
影响因子：
3.5
作者：
Costa, Yael;Speed, Robert M.;Cooke, Howard J.
通讯作者：
Cooke, Howard J.
DOI：
10.1095/biolreprod2.1.114
发表时间：
1970-01-01
期刊：
Biology Reprod.
影响因子：
--
作者：
Eddy, E. M.
通讯作者：
Eddy, E. M.
DOI：
10.1073/pnas.0510999103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Iguchi, Naoko;Tobias, John W.;Hecht, Norman B.
通讯作者：
Hecht, Norman B.