|ZFIN ID: ZDB-PUB-200810-13|
Thyroid hormone receptor α mutations cause heart defects in zebrafish
Han, C.R., Wang, H., Hoffmann, V., Zerfas, P., Kruhlak, M., Cheng, S.Y.
|Source:||Thyroid : official journal of the American Thyroid Association 31(2): 315-326 (Journal)|
|Registered Authors:||Cheng, Sheue-yann|
|PubMed:||32762296 Full text @ Thyroid|
Han, C.R., Wang, H., Hoffmann, V., Zerfas, P., Kruhlak, M., Cheng, S.Y. (2020) Thyroid hormone receptor α mutations cause heart defects in zebrafish. Thyroid : official journal of the American Thyroid Association. 31(2):315-326.
Background Mutations of thyroid hormone receptor alpha 1 (TRalpha1) cause resistance to thyroid hormone (RTHalpha). Patients exhibit growth retardation, delayed bone development, anemia, and bradycardia. By using mouse models of RTHalpha much has been learned about the molecular actions of TRalpha 1 mutants that underlie these abnormalities in adults. Using zebrafish models of RTHalpha that we have recently created, we aimed to understand how TRalpha1 mutants affect the heart function during this period.
Methods In contrast to human and mice, the thra gene is duplicated, thraa and thrab, in zebrafish. Using CRISPR/Cas9-mediated targeted mutagenesis, we created C-terminal mutations in the each of two duplicated thra genes in zebrafish (thraa 8-bp insertion or thrab 1-bp insertion mutations). We recently showed that these mutant fish faithfully recapitulated growth retardation as found in patients and thra mutant mice. In the present studies, we used histological analysis, gene expression profiles, confocal fluorescence and transmission electron microscopy (TEM) to comprehensively analyze the phenotypic characteristics of mutant fish heart during development.
Results We found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and decreased circulating blood speed and reduced expression of contractile genes indicated the weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days post fertilization (juveniles). Further, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by TEM. The abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish.
Conclusions Using a zebrafish model of RTHalpha, the present studies demonstrated for the first time that TRalpha mutants could act to cause abnormal heart structure, weaken contractility and disrupt sarcomere organization that affect heart functions. These findings provide new insights into the bradycardia found in RTHalpha patients.