The TDRD9-MIWI2 Complex Is Essential for piRNA-Mediated Retrotransposon Silencing in the Mouse Male Germline
The TDRD9-MIWI2 Complex Is Essential for piRNA-Mediated Retrotransposon Silencing in the Mouse Male Germline
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DOI：
10.1016/j.devcel.2009.10.012
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发表时间：
2009-12-15
影响因子：
11.8
通讯作者：
Chuma, Shinichiro
中科院分区：
文献类型：
--
作者：
Shoji, Masanobu;Tanaka, Takashi;Chuma, Shinichiro
针对转座元件的宿主防御机制对于保护基因组信息至关重要。在这里，我们证明包含 9 (Tdrd9) 的 tudor 结构域对于沉默小鼠雄性种系中的 Line-1 逆转录转座子至关重要。 Tdrd9 编码 ATPase/DExH 型解旋酶，其突变导致雄性不育，表现为减数分裂失败。在 Tdrd9 突变体中，Line-1 被高度激活，并且与 Line-1 相对应的 piwi 相互作用小 RNA (piRNA) 增加，表明前馈放大在突变体中起作用。在胎儿睾丸中，Tdrd9 突变会导致 Line-1 去沉默和原精原细胞中异常的 piRNA 图谱，随后导致同源 DNA 去甲基化。 TDRD9 与 MIWI2 复合，在加工体中具有明显的区室化，并且这种 TDRD9-MIWI2 定位受到位于线粒体间水泥中的 MILI 和 TDRD1 的调节。我们的结果将 TDRD9 确定为 MIWI2 的功能伙伴，并表明 tudor-piwi 关联是一个保守特征，而两个独立的轴 TDRD9-MIWI2 和 TDRD1-MILI 在小鼠雄性种系的 piwi-小 RNA 通路中非冗余地合作。
Host-defense mechanisms against transposable elements are critical to protect the genome information. Here we show that tudor-domain containing 9 (Tdrd9) is essential for silencing Line-1 retrotransposon in the mouse male germline. Tdrd9 encodes an ATPase/DExH-type helicase, and its mutation causes male sterility showing meiotic failure. In Tdrd9 mutants, Line-1 was highly activated and piwi-interacting small RNAs (piRNAs) corresponding to Line-1 were increased, suggesting that feedforward amplification operates in the mutant. In fetal testes, Tdrd9 mutation causes Line-1 desilencing and an aberrant piRNA profile in prospermatogonia, followed by cognate DNA demethylation. TDRD9 complexes with MIWI2 with distinct compartmentalization in processing bodies, and this TDRD9-MIWI2 localization is regulated by MILI and TDRD1 residing at intermito-chondrial cement. Our results identify TDRD9 as a functional partner of MIWI2 and indicate that the tudor-piwi association is a conserved feature, while two separate axes, TDRD9-MIWI2 and TDRD1-MILI, cooperate nonredundantly in the piwi-small RNA pathway in the mouse male germline.