Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain.
Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain.
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DOI：
10.1186/s12915-017-0387-1
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发表时间：
2017-06-29
期刊：
影响因子：
5.4
通讯作者：
Ceman S
中科院分区：
文献类型：
--
作者：
Skariah G;Seimetz J;Norsworthy M;Lannom MC;Kenny PJ;Elrakhawy M;Forsthoefel C;Drnevich J;Kalsotra A;Ceman S
莫洛尼白血病病毒10（Mov 10）是一种RNA解旋酶，介导RNA诱导的沉默复合物进入信使RNA（mRNA）。到目前为止，其作为RNA解旋酶和作为逆转录转座子的调节剂的作用仅在细胞系中表征。我们研究了Mov 10在小鼠大脑中的作用，通过检查其在发育过程中的表达，并试图创建一个Mov 10基因敲除小鼠。两个Mov 10拷贝的丢失导致早期胚胎死亡。Mov 10在出生后的小鼠脑中显著升高，在那里它结合retroelement RNA和mRNA。Mov 10通过直接抑制互补DNA合成来抑制细胞核中的逆转录因子，而胞质Mov 10调节细胞骨架mRNA来影响神经突生长。我们通过观察Mov 10杂合子小鼠海马神经元中树突分支减少和Mov 10敲除Neuro 2A细胞中神经突缩短来验证这一重要功能。敲除Fmrp也导致神经突缩短。Mov 10、Fmrp和Ago 2在大脑中结合了一组共同的mRNA。小鼠大脑中Mov 10的减少导致焦虑和在新环境中的活动增加，支持其在正常脑回路发育中的重要作用。Mov 10对正常的神经元发育和大脑功能至关重要。Mov 10优先结合参与肌动蛋白结合、神经元投射和细胞骨架的RNA。这是Mov 10在神经元发育中的一个全新且至关重要的功能，并为Mov 10成为具有潜在细胞结构原因（如自闭症和阿尔茨海默病）的神经系统疾病的重要候选人奠定了先例。本文的在线版本（doi：10.1186/s12915-017-0387-1）包含补充材料，可供授权用户使用。
Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality. Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry. Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer’s disease. The online version of this article (doi:10.1186/s12915-017-0387-1) contains supplementary material, which is available to authorized users.