Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.
Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.
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DOI：
10.1016/j.isci.2021.103463
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发表时间：
2021-12-17
期刊：
影响因子：
5.8
通讯作者：
Cunningham TJ
中科院分区：
文献类型：
--
作者：
Devoy A;Price G;De Giorgio F;Bunton-Stasyshyn R;Thompson D;Gasco S;Allan A;Codner GF;Nair RR;Tibbit C;McLeod R;Ali Z;Noda J;Marrero-Gagliardi A;Brito-Armas JM;Williams C;Öztürk MM;Simon M;O'Neill E;Bryce-Smith S;Harrison J;Atkins G;Corrochano S;Stewart M;Gilthorpe JD;Teboul L;Acevedo-Arozena A;Fisher EMC;Cunningham TJ
肌萎缩侧索硬化症/额颞叶痴呆（ALS/FTD）是一种致命的神经退行性疾病，需要持续的创新来提高认识和开发治疗方法。通过将Sod1， Tardbp （TDP-43）和Fus的小鼠基因组区域替换为人类同源物，我们创建了下一代基因组人源化敲入小鼠模型，保留了人类蛋白质的生物化学和外显子和内含子的剪接。我们建立了一个大敲入等位基因质量控制的新标准，展示了间接捕获在牛津纳米孔测序之后富集感兴趣的基因组区域的效用。广泛的分析表明，纯合子人源化动物只在内源性水平上表达人蛋白。人源化FUS动物的特征表明，它们在整个生命周期中表型正常。这些人源化菌株对于干预措施的临床前评估至关重要，并可作为添加编码或非编码人类ALS/FTD突变的模板，以在生理背景下解剖疾病的病理机制。用同源人类基因组序列替代小鼠Sod1、Tardbp和Fus敲入等位基因，使用靶向长读测序对敲入等位基因进行彻底的等位基因QC，小鼠是有活力的、可生育的，并为ALS/FTD研究提供了完善的工具。神经科学;生物模型
Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context. Replacement in mice of Sod1, Tardbp, and Fus with orthologous human genomic sequence Thorough allele QC of knockin alleles using targeted long-read sequencing Mice are viable, fertile, and provide refined tools for ALS/FTD research Aging of hFUS mice reveals no overt phenotype and minimal transcriptomic disruption Neurogenetics; Neuroscience; Model organism
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影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
DOI：
10.15252/embj.201798684
发表时间：
2018-06-01
期刊：
The EMBO journal
影响因子：
--
作者：
Fratta P;Sivakumar P;Humphrey J;Lo K;Ricketts T;Oliveira H;Brito-Armas JM;Kalmar B;Ule A;Yu Y;Birsa N;Bodo C;Collins T;Conicella AE;Mejia Maza A;Marrero-Gagliardi A;Stewart M;Mianne J;Corrochano S;Emmett W;Codner G;Groves M;Fukumura R;Gondo Y;Lythgoe M;Pauws E;Peskett E;Stanier P;Teboul L;Hallegger M;Calvo A;Chiò A;Isaacs AM;Fawzi NL;Wang E;Housman DE;Baralle F;Greensmith L;Buratti E;Plagnol V;Fisher EM;Acevedo-Arozena A
通讯作者：
Acevedo-Arozena A
影响因子：
3.7
作者：
Dib, Samar;Xiao, Shangxi;Robertson, Janice
通讯作者：
Robertson, Janice
DOI：
10.1016/j.molbrainres.2004.07.002
发表时间：
2004-11-04
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Alexander, GM;Erwin, KL;Heiman-Patterson, TD
通讯作者：
Heiman-Patterson, TD
影响因子：
14.9
作者：
Humphrey, Jack;Birsa, Nicol;Fratta, Pietro
通讯作者：
Fratta, Pietro