Abstract
Adaptor proteins play crucial roles in signal transduction across diverse signaling pathways. Src-homology 2 domain-containing E (SH2E) is the adaptor protein highly expressed in vascular endothelial cells and myocardium during zebrafish embryogenesis. In this study we investigated the function and mechanisms of SH2E in cardiogenesis. We first analyzed the spatiotemporal expression of SH2E and then constructed zebrafish lines with SH2E deficiency using the CRISPR-Cas9 system. We showed that homozygous mutants developed progressive pericardial edema (PCE), dilated atrium, abnormal atrioventricular looping and thickened atrioventricular wall from 3 days post fertilization (dpf) until death; inducible overexpression of SH2E was able to partially rescue the PCE phenotype. Using transcriptome sequencing analysis, we demonstrated that the MAPK/ERK and NF-κB signaling pathways might be involved in SH2E-deficiency-caused PCE. This study underscores the pivotal role of SH2E in cardiogenesis, and might help to identify innovative diagnostic techniques and therapeutic strategies for congenital heart disease.
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Acknowledgements
We thank Dr. Nathan Lawson from UMass Chan Medical School and Dr. Jing-wei Xiong from Peking University for providing the Tg(fli1:EGFP) fish line and CRISPR/Cas9 plasmids, respectively. This work was funded by the National Key Research and Development Program of China (2019YFA0802700), the National Natural Science Foundation of China (92168206, 82400541) and the Postdoctoral Fellowship Program of CPSF under Grant Number GZC20242284.
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QJ, YLL and JC conceived and designed the project. YLL carried out the experiments and analyzed the data. YXH and HMY contributed to confirming and maintaining the knockout line. YXH helped to perform the pharmacological treatment and analyze the data. FFL and JC directed the FISH analysis. ZFG supported the zebrafish platform. CL supervised the study. YLL and YXH drafted the manuscript. YLL, YXH and FFL reviewed and edited the manuscript. QJ supervised the study and edited the manuscript.
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The authors declare no conflict of interest. Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences has applied for a patent, China Patent Application No. 202311014379.7 by inventors Qing Jing, Yang-xi Hu, Yu-lai Liang and Zhi-hua Liu for the usage of L-selenomethionine in antioxidant stress and alleviation of cardiac developmental defects caused by SH2E gene mutations described in this paper under the support of the Program of EnShi TuJia and Miao Autonomous Prefecture Bureau of Scientific and Technological Affairs.
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Liang, Yl., Hu, Yx., Li, Ff. et al. Adaptor protein Src-homology 2 domain containing E (SH2E) deficiency induces heart defect in zebrafish. Acta Pharmacol Sin 46, 404–415 (2025). https://doi.org/10.1038/s41401-024-01392-8
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DOI: https://doi.org/10.1038/s41401-024-01392-8
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