Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.
Cognitive Function Related to the Sirh11/Zcchc16 Gene Acquired from an LTR Retrotransposon in Eutherians.
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DOI：
10.1371/journal.pgen.1005521
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Kaneko-Ishino T
中科院分区：
文献类型：
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作者：
Irie M;Yoshikawa M;Ono R;Iwafune H;Furuse T;Yamada I;Wakana S;Yamashita Y;Abe T;Ishino F;Kaneko-Ishino T
小鼠 Sushi-i chi 相关逆转录转座子同源物 11 / Z inc Finger CCHC 结构域 16 (Sirh11/Zcchc16) 的基因靶向导致与认知相关的异常行为，包括注意力、冲动性和工作记忆。 Sirh11/Zcchc16 编码 CCHC 型锌指蛋白，与 LTR 逆转录转座子 Gag 蛋白具有高度同源性。对前额皮质区域进行微透析分析，敲除（KO）小鼠灌注高钾人工脑脊液后，去甲肾上腺素（NA）的回收率较多巴胺（DA）降低。这些数据表明，在当代小鼠发育系统中，Sirh11/Zcchc16 可能通过去甲肾上腺素能系统参与大脑的认知功能。有趣的是，它在真兽类的四个主要类群中的三个中高度保守，即真兽类、劳亚兽类和非洲兽类，但在树懒和犰狳等异种动物中却发生了严重突变，这表明它对包括人类和小鼠在内的三个主要真兽类谱系的大脑进化做出了贡献。 Sirh11/Zcchc16 是第一个参与大脑功能的 SIRH 基因，而不仅仅是胎盘基因，如 Peg10、Peg11/Rtl1 和 Sirh7/Ldoc1 中所见。逆转录转座子衍生的 DNA 序列约占哺乳动物基因组的 40%，而蛋白质编码基因仅占 1.5%。它们通常被认为是“垃圾DNA”，甚至对宿主生物体具有潜在危害。然而，一系列敲除 (KO) 小鼠分析表明，至少一些 LTR 逆转录转座子和逆转录病毒衍生序列作为内源基因在当前哺乳动物发育系统中发挥着重要作用，例如 Peg10、Peg11/Rtl1、Sirh7/Ldoc1、SYNCYTIN 和 FEMATRIN-1，它们在胎盘功能的多个方面都有活性。在这里，我们证明了另一个 LTR 逆转录转座子衍生基因 Sirh11/Zcchc16 在大脑认知功能中发挥着重要作用。 Sirh11/Zcchc16 KO小鼠表现出与认知相关的异常行为，包括注意力、冲动和工作记忆，可能是由于蓝斑-去甲肾上腺素（LC-NA）系统所致，表明人类SIRH11/ZCCHC16可能与X连锁智力障碍和/或注意力缺陷/多动障碍有关。比较基因组分析表明，SIRH11/ZCCHC16 是在真兽类共同祖先中获得的，这表明它有助于真兽类大脑进化，因为它在日常生活中发生的竞争中赋予了至关重要的优势。这项研究进一步深入了解了 LTR 逆转录转座子衍生基因对哺乳动物进化的影响。
Gene targeting of mouse S ushi- i chi-related r etrotransposon h omologue 11 / Z inc finger CCHC domain-containing 16 (Sirh11/Zcchc16) causes abnormal behaviors related to cognition, including attention, impulsivity and working memory. Sirh11/Zcchc16 encodes a CCHC type of zinc-finger protein that exhibits high homology to an LTR retrotransposon Gag protein. Upon microdialysis analysis of the prefrontal cortex region, the recovery rate of noradrenaline (NA) was reduced compared with dopamine (DA) after perfusion of high potassium-containing artificial cerebrospinal fluid in knockout (KO) mice. These data indicate that Sirh11/Zcchc16 is involved in cognitive function in the brain, possibly via the noradrenergic system, in the contemporary mouse developmental systems. Interestingly, it is highly conserved in three out of the four major groups of the eutherians, euarchontoglires, laurasiatheria and afrotheria, but is heavily mutated in xenarthran species such as the sloth and armadillo, suggesting that it has contributed to brain evolution in the three major eutherian lineages, including humans and mice. Sirh11/Zcchc16 is the first SIRH gene to be involved in brain function, instead of just the placenta, as seen in the case of Peg10, Peg11/Rtl1 and Sirh7/Ldoc1. Retrotransposon-derived DNA sequences occupy approximately 40% of the mammalian genome, compared with only 1.5% of protein coding genes. They have been commonly considered “junk DNA” and even potentially harmful for host organisms. However, a series of knockout (KO) mouse analyses demonstrated that at least some of the LTR retrotransposon- and retrovirus-derived sequences play essential roles in the current mammalian developmental system as endogenous genes, such as Peg10, Peg11/Rtl1, Sirh7/Ldoc1, SYNCYTINs and FEMATRIN-1, which are active in multiple aspects of placental function. Here we demonstrate that another LTR retrotransposon-derived gene, Sirh11/Zcchc16, plays an important role in cognitive function in the brain. Sirh11/Zcchc16 KO mice exhibit abnormal behaviors related to cognition, including attention, impulsivity and working memory, possibly due to the locus coeruleus-noradrenaline (LC-NA) system, suggesting that human SIRH11/ZCCHC16 may be involved in X-linked intellectual disability and/or attention-deficit/hyperactivity disorder. Comparative genome analysis demonstrates that SIRH11/ZCCHC16 was acquired in a common eutherian ancestor, suggesting that it contributed to eutherian brain evolution because it confers a critically important advantage in the competition that occurs in daily life. This study provides further insight into the impact of LTR retrotransposon-derived genes on mammalian evolution.