PUBLICATION

Cardiac Na+-Ca2+ exchanger 1 (ncx1h) is critical for the ventricular cardiomyocyte formation via regulating the expression levels of gata4 and hand2 in zebrafish

Authors
Chu, L., Yin, H., Gao, L., Gao, L., Xia, Y., Zhang, C., Chen, Y., Liu, T., Huang, J., Boheler, K.R., Zhou, Y., Yang, H.T.
ID
ZDB-PUB-200711-10
Date
2020
Source
Science China. Life sciences   64(2): 255-268 (Journal)
Registered Authors
Chen, Yi
Keywords
Ca2+ transport protein, gata4, hand2, ncx1h, ventricular cardiomyocyte formation, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Basic Helix-Loop-Helix Transcription Factors/genetics*
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Calcium/metabolism
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • GATA Transcription Factors/genetics*
  • GATA Transcription Factors/metabolism
  • Gene Expression Regulation, Developmental*
  • Heart Ventricles/cytology
  • Heart Ventricles/embryology
  • Heart Ventricles/metabolism
  • In Situ Hybridization
  • Microscopy, Confocal
  • Mutation
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism*
  • Organogenesis/genetics
  • Sodium-Calcium Exchanger/genetics*
  • Sodium-Calcium Exchanger/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed
32648190 Full text @ Sci. China Ser. C-Life Sci.
Abstract
Ca2+ signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca2+ transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca2+ efflux in cardiomyocytes. It is involved in cardiogenesis, while the mechanism is unclear. Here, using the forward genetic screening in zebrafish, we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene (mutantLDD353/ncx1hL154P) that led to smaller hearts with reduced heart rate and weak contraction. Mechanistically, the number of ventricular but not atrial cardiomyocytes was reduced in ncx1hL154P zebrafish. These defects were mimicked by knockdown or knockout of ncx1h. Moreover, ncx1hL154P had cytosolic and mitochondrial Ca2+ overloading and Ca2+ transient suppression in cardiomyocytes. Furthermore, ncx1hL154P and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions, while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes. These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish, and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping