Zebrafish Foxc1a controls ventricular chamber maturation by directly regulating <i>wwtr1</i> and <i>nkx2.5</i> expression

Luqingqing He; Qinxin Zhang; Dongya Jiang; Yunfeng Zhang; Yuxuan Wei; Yuxi Yang; Nan Li; Shuang Wang; Yunyun Yue; Qingshun Zhao

doi:10.1016/j.jgg.2021.12.002

Volume 49 Issue 6

Jun. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(6): 559-568

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Zebrafish Foxc1a controls ventricular chamber maturation by directly regulating wwtr1 and nkx2.5 expression

doi: 10.1016/j.jgg.2021.12.002

a. Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu 210061, China;
b. Department of Prenatal Diagnosis, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu 210004, China;
c. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China

Funds:

This work was supported by the National Natural Science Foundation of China (31970769 and 31671518). We thank Dr. Jingwei Xiong from Peking University for providing us with the transgenic zebrafish line Tg(myl7:eGFP). We thank Dr. Dong Liu from Zebrafish Center at Nantong University Jiangsu Key Laboratory of Neuroregeneration for providing the transgenic zebrafish lines Tg(myl7:nDsRed) and Tg(kdrl:ras-mCherry). We thank members of Xin Lou Lab at Nanjing University for the help during this project. We thank Dr. Xiaohua Dong from the Department of Pediatric, Jingjiang Peopleʼs Hospital Affiliated to Yangzhou University for constructive discussions of this project. The authors would also like to express their gratitude to AJE (https://www.aje.cn/) for the expert linguistic services provided.

Received Date: 2021-07-06
Revised Date: 2021-12-06
Accepted Date: 2021-12-06
Publish Date: 2022-06-30

Abstract

Abstract

Chamber maturation is a significant process in cardiac development. Disorders of this crucial process lead to a range of congenital heart defects. Foxc1a is a critical transcription factor reported to regulate the specification of cardiac progenitor cells. However, little is known about the role of Foxc1a in modulating chamber maturation. Previously, we reported that foxc1a-null zebrafish embryos exhibit disrupted heart structures and functions. In this study, we observe that ventricle structure and cardiomyocyte proliferation are abolished during chamber maturation in foxc1a-null zebrafish embryos. To observe the endogenous localization of Foxc1a in the hearts of living embryos, we insert eyfp at the foxc1a genomic locus using TALEN. Analysis of the knockin zebrafish show that foxc1a is widely expressed in ventricular cardiomyocytes during chamber development. Cardiac RNA sequencing analysis reveals the downregulated expression of the Hippo signaling effector wwtr1. Dual-luciferase and chromatin immunoprecipitation assays reveal that Foxc1a can bind directly to three sites in the wwtr1 promoter region. Furthermore, wwtr1 mRNA overexpression is sufficient to reverse the ventricle defects during chamber maturation. Conditional overexpression of nkx2.5 also partially rescues the ventricular defects during chamber development. These findings demonstrate that wwtr1 and nkx2.5 are direct targets of Foxc1a during ventricular chamber maturation.
- Zebrafish,
- Foxc1a,
- Cardiac ventricular development,
- wwtr1,
- nkx2.5

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References(52)

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