title: Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish.
abstract: Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium-calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Langenbacher
authors.forename: Yuan
authors.initials: Y
authors.lastname: Dong
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shu
authors.forename: Jayoung
authors.initials: J
authors.lastname: Choi
authors.forename: Debora A
authors.initials: DA
authors.lastname: Nicoll
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D006706:Homeostasis; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D010802:Phylogeny; D012313:RNA / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*
chemical_list: D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D012313:RNA; D002118:Calcium