Generation of a thrombopoietin‐deficient thrombocytopenia model in zebrafish
Generation of a thrombopoietin‐deficient thrombocytopenia model in zebrafish
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斑马鱼血小板生成素缺陷型血小板减少症模型的生成
DOI：
10.1111/jth.15772
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发表时间：
2022-05
影响因子：
10.4
通讯作者：
Yiyue Zhang
中科院分区：
文献类型：
--
作者：
Lian Yang;Liangliang Wu;Panpan Meng;Xuebing Zhang;Dejian Zhao;Q Lin;Yiyue Zhang
血小板的生成受血小板生成素（THPO）的严格调节。THPO基因突变导致血小板减少症。尽管缺乏Thpo的小鼠存在血小板减少症，但预测小鼠中新型THPO突变的表型和致病性是有限的。斑马鱼是快速验证和研究人类血液病候选基因的有力工具，已被用作人类血小板减少症的模型，本研究旨在探讨Thpo在斑马鱼血小板生成中的作用，并建立Thpo缺陷的斑马鱼模型。该模型可用于阐明临床发现的人类THPO变体，其临床意义未知，并评估THPO受体激动剂（THPO-Ras）的作用，以及新药筛选平台。在破坏斑马鱼thpo后，thposzy 6斑马鱼呈现出thpo表达的显著减少并发展为血小板减少症。此外，我们对thposzy 6突变的斑马鱼进行了体内研究，发现了两个人类临床点突变（c.091C > T和c.112C > T），这两个点突变是导致血小板减少症表型的原因。此外，在Tg（mpl：eGFP）; thposzy 6系中评价了用作抗血小板减少症的治疗剂的THPO-RA的作用。具有突变thposzy 6的斑马鱼呈现出thpo表达的显著降低并发展为血小板减少症。Thpo功能丧失斑马鱼模型可作为研究thpo缺乏引起的血小板减少症的有价值的临床前模型，以及研究人类临床THPO变体和评估THPO-RA效果的工具。
The production of platelets is tightly regulated by thrombopoietin (THPO). Mutations in the THPO gene cause thrombocytopenia. Although mice lacking Thpo present with thrombocytopenia, predicting phenotypes and pathogenicity of novel THPO mutations in mice is limited. Zebrafish can be a powerful tool for fast validation and study of candidate genes of human hematological diseases and have already been used as a model of human thrombocytopenia.We aim to investigate the role of Thpo in zebrafish thrombopoiesis and to establish a Thpo-deficient zebrafish model. The model could be applied for illustrating the clinically discovered human THPO variants of which the clinical significance is not known and to evaluate the effect of THPO receptor agonists (THPO-Ras), as well as a screening platform for new drugs.We generated a thpo loss-of-function zebrafish model using CRISPR/Cas9. After disruption of zebrafish thpo, thposzy6 zebrafish presented with a significant reduction of thpo expression and developed thrombocytopenia. Furthermore, we performed in vivo studies with zebrafish with the thposzy6 mutation and found two human clinical point mutations (c.091C > T and c.112C > T) that were responsible for the thrombocytopenia phenotype. In addition, effects of THPO-RAs used as therapeutics against thrombocytopenia were evaluated in the Tg(mpl:eGFP);thposzy6 line.Zebrafish with the mutation thposzy6 presented with a significant reduction of thpo expression and developed thrombocytopenia. Thpo loss-of-function zebrafish model can serve as a valuable preclinical model for thrombocytopenia caused by thpo-deficiency, as well as a tool to study human clinical THPO variants and evaluate the effect of THPO-RAs.
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影响因子：
4.5
作者：
Katsube, Takayuki;Ishibashi, Toru;Wajima, Toshihiro
通讯作者：
Wajima, Toshihiro
DOI：
--
发表时间：
2013
期刊：
--
影响因子：
--
作者：
Woong Y. Hwang;Yanfang Fu;D. Reyon;Morgan L. Maeder;S. Tsai;Jeffry D. Sander;R. Peterson;J.-R. Joanna Yeh-J.
通讯作者：
Woong Y. Hwang;Yanfang Fu;D. Reyon;Morgan L. Maeder;S. Tsai;Jeffry D. Sander;R. Peterson;J.-R. Joanna Yeh-J.
影响因子：
64.8
作者：
DESAUVAGE, FJ;HASS, PE;EATON, DL
通讯作者：
EATON, DL
影响因子：
3.8
作者：
Jing Li;Panpan Meng;R. Zhou;Yiyue Zhang;Qing Lin
通讯作者：
Jing Li;Panpan Meng;R. Zhou;Yiyue Zhang;Qing Lin
影响因子：
6.7
作者：
Sacks, David;Baxter, Blaise;Vorwerk, Dierk
通讯作者：
Vorwerk, Dierk