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
{"title":"Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity","authors":"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","doi":"10.1016/j.pneurobio.2024.102568","DOIUrl":null,"url":null,"abstract":"<div><p>The <u>Top</u>oisomerase <u>3B</u> (Top3b) - <u>T</u>u<u>d</u>o<u>r d</u>omain containing <u>3</u><span> (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. </span><em>TOP3B</em><span> mutations in humans are associated with schizophrenia<span><span>, autism and </span>cognitive disorders; and </span></span><em>Top3b</em><span>-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors<span>, aberrant neurogenesis<span> and synaptic plasticity, and transcriptional defects. Similarly, human </span></span></span><em>TDRD3</em> genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of <em>Tdrd3</em> in normal brain function has not been examined in animal models. Here we generated a <em>Tdrd3</em>-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to <em>Top3b-</em>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 <em>Tdrd3</em><span><span>-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction<span>, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for </span></span>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.</span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Progress in Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0301008224000042","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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.