Tdrd3缺失小鼠表现出与神经发生和突触可塑性相关的转录后和行为障碍

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2024-01-10 DOI:10.1016/j.pneurobio.2024.102568
Xingliang Zhu , Yuyoung Joo , Simone Bossi , Ross A. McDevitt , Aoji Xie , Yue Wang , Yutong Xue , Shuaikun Su , Seung Kyu Lee , Nirnath Sah , Shiliang Zhang , Rong Ye , Alejandro Pinto , Yongqing Zhang , Kimi Araki , Masatake Araki , Marisela Morales , Mark P. Mattson , Henriette van Praag , Weidong Wang
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引用次数: 0

摘要

拓扑异构酶 3B(TOP3B)--含都铎结构域 3(Tdrd3)蛋白复合物是动物体内唯一能改变 DNA 和 RNA 拓扑的双活性拓扑异构酶复合物。人类的 TOP3B 基因突变与精神分裂症、自闭症和认知障碍有关;TOP3b 基因缺失的小鼠表现出在精神和认知障碍动物模型中观察到的几种表型,包括认知和情感行为受损、神经发生和突触可塑性异常以及转录缺陷。同样,人类 TDRD3 基因组变异也与精神分裂症、言语短期记忆和教育程度有关。然而,Tdrd3 在正常大脑功能中的重要性尚未在动物模型中得到研究。在这里,我们产生了一个 Tdrd3 基因缺失小鼠品系,并证明与 Top3b 基因缺失小鼠相比,这些小鼠显示出共同和独特的缺陷。在认知行为、突触可塑性、成神经发生、新生神经元形态和神经元活动依赖性转录等方面观察到了共同的缺陷;而 Tdrd3 缺失小鼠特有的缺陷包括多动、焦虑样行为变化、嗅觉、新生神经元复杂性增加和髓鞘化减少。有趣的是,多个对神经发育和认知功能至关重要的基因表现出成熟转录本水平降低,而非新生转录本水平降低。我们推断,整个 Top3b-Tdrd3 复合物对正常的大脑功能至关重要,转录后调控缺陷可能导致认知和精神疾病。
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Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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