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Cardiac Na + -Ca 2+ exchanger 1 (ncx1h) is critical for the ventricular cardiomyocyte formation via regulating the expression levels of gata4 and hand2 in zebrafish.
- Source :
-
Science China. Life sciences [Sci China Life Sci] 2021 Feb; Vol. 64 (2), pp. 255-268. Date of Electronic Publication: 2020 Jul 07. - Publication Year :
- 2021
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Abstract
- Ca <superscript>2+</superscript> signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca <superscript>2+</superscript> transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca <superscript>2+</superscript> 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 (mutant <superscript>LDD353</superscript> /ncx1h <superscript>L154P</superscript> ) that led to smaller hearts with reduced heart rate and weak contraction. Mechanistically, the number of ventricular but not atrial cardiomyocytes was reduced in ncx1h <superscript>L154P</superscript> zebrafish. These defects were mimicked by knockdown or knockout of ncx1h. Moreover, ncx1h <superscript>L154P</superscript> had cytosolic and mitochondrial Ca <superscript>2+</superscript> overloading and Ca <superscript>2+</superscript> transient suppression in cardiomyocytes. Furthermore, ncx1h <superscript>L154P</superscript> 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.
- Subjects :
- Animals
Animals, Genetically Modified
Basic Helix-Loop-Helix Transcription Factors metabolism
Calcium metabolism
Embryo, Nonmammalian cytology
Embryo, Nonmammalian embryology
Embryo, Nonmammalian metabolism
GATA Transcription Factors metabolism
Heart Ventricles cytology
Heart Ventricles embryology
Heart Ventricles metabolism
In Situ Hybridization
Microscopy, Confocal
Mutation
Myocytes, Cardiac cytology
Organogenesis genetics
Sodium-Calcium Exchanger metabolism
Zebrafish embryology
Zebrafish metabolism
Zebrafish Proteins metabolism
Basic Helix-Loop-Helix Transcription Factors genetics
GATA Transcription Factors genetics
Gene Expression Regulation, Developmental
Myocytes, Cardiac metabolism
Sodium-Calcium Exchanger genetics
Zebrafish genetics
Zebrafish Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1869-1889
- Volume :
- 64
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Science China. Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32648190
- Full Text :
- https://doi.org/10.1007/s11427-019-1706-1