Generation of a thrombopoietin-deficient thrombocytopenia model in zebrafish
© 2022 International Society on Thrombosis and Haemostasis..
BACKGROUND: 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.
OBJECTIVES: 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.
METHODS: 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.
RESULTS AND CONCLUSIONS: 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 20(2022), 8 vom: 13. Aug., Seite 1900-1909 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Lian [VerfasserIn] |
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| Links: |
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| Themen: |
9014-42-0 |
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| Anmerkungen: |
Date Completed 22.07.2022 Date Revised 29.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/jth.15772 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM341443778 |
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| 100 | 1 | |a Yang, Lian |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Generation of a thrombopoietin-deficient thrombocytopenia model in zebrafish |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 22.07.2022 | ||
| 500 | |a Date Revised 29.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 International Society on Thrombosis and Haemostasis. | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a OBJECTIVES: 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a RESULTS AND CONCLUSIONS: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Thpo | |
| 650 | 4 | |a Disease model | |
| 650 | 4 | |a Human clinical variants | |
| 650 | 4 | |a Thrombocytopenia | |
| 650 | 4 | |a Zebrafish | |
| 650 | 7 | |a Receptors, Thrombopoietin |2 NLM | |
| 650 | 7 | |a Thrombopoietin |2 NLM | |
| 650 | 7 | |a 9014-42-0 |2 NLM | |
| 700 | 1 | |a Wu, Liangliang |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Panpan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xuebing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Dejian |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yiyue |e verfasserin |4 aut | |
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