PUBLICATION

Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish

Authors

Becker, J.R., Deo, R.C., Werdich, A.A., Panàkovà, D., Coy, S., and MacRae, C.A.

ID

ZDB-PUB-110124-3

Date

2011

Source

Disease models & mechanisms 4(3): 400-410 (Journal)

Registered Authors

MacRae, Calum A., Panáková, Daniela

Keywords

none

Datasets

GEO:GSE20179

MeSH Terms

Embryo, Nonmammalian/drug effects
Embryo, Nonmammalian/metabolism
Embryo, Nonmammalian/pathology
Mice
Troponin T/chemistry
Troponin T/genetics
Organogenesis*/drug effects
Amino Acid Sequence
Molecular Sequence Data
Sarcomeres/drug effects
Sarcomeres/pathology
Calcium/metabolism
Mutation/genetics*
Myocardial Contraction/drug effects
Cardiomyopathy, Hypertrophic/complications
Cardiomyopathy, Hypertrophic/genetics*
Cardiomyopathy, Hypertrophic/pathology*
Cardiomyopathy, Hypertrophic/physiopathology
Heart Ventricles/drug effects
Heart Ventricles/pathology
Heart Ventricles/physiopathology
Heart/drug effects
Heart/embryology*
Heart/physiopathology
Myocytes, Cardiac/metabolism
Myocytes, Cardiac/pathology*
Alternative Splicing/drug effects
Alternative Splicing/genetics
Zebrafish Proteins/chemistry
Zebrafish Proteins/genetics
Oligonucleotides, Antisense/pharmacology
Animals
Transcription, Genetic/drug effects
Hyperplasia/complications
Hyperplasia/pathology
Gene Expression Regulation, Developmental/drug effects
Zebrafish/embryology*
Zebrafish/genetics
Humans

(all 39)

PubMed

21245263 Full text @ Dis. Model. Mech.

Abstract

To assess the effects during cardiac development of mutations that cause human cardiomyopathy, we modeled a sarcomeric gene mutation in the embryonic zebrafish. We designed morpholino antisense oligonucleotides targeting the exon 13 splice donor site in the zebrafish cardiac troponin T (tnnt2) gene, in order to precisely recapitulate a human TNNT2 mutation that causes hypertrophic cardiomyopathy (HCM). HCM is a disease characterized by myocardial hypertrophy, myocyte and myofibrillar disarray, as well as an increased risk of sudden death. Similar to humans with HCM, the morphant zebrafish embryos displayed sarcomere disarray and there was a robust induction of myocardial hypertrophic pathways. Microarray analysis uncovered a number of shared transcriptional responses between this zebrafish model and a well-characterized mouse model of HCM. However, in contrast to adult hearts, these embryonic hearts developed cardiomyocyte hyperplasia in response to this genetic perturbation. The re-creation of a human disease-causing TNNT2 splice variant demonstrates that sarcomeric mutations can alter cardiomyocyte biology at the earliest stages of heart development with distinct effects from those observed in adult hearts despite shared transcriptional responses.

Genes / Markers

Figures