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PLoS Genet. 2018 Jul 6;14(7):e1007502. doi: 10.1371/journal.pgen.1007502. eCollection 2018 Jul.

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.

Author information

1
Aix-Marseille Université, CNRS UMR 7288, IBDM, Marseille, France.
2
Aix-Marseille Université, INSERM UMR 1090, TAGC, Marseille, France.
3
INSERM, CNRS, Université de Montpellier, PHYMEDEXP, Montpellier, France.
4
Aix-Marseille Université, CNRS, CRMBM, Marseille, France.
5
Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
6
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
7
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst NSW, Australia.
8
St. Vincent's Clinical School and School of Biological and Biomolecular Sciences, University of New South Wales, Kensington, Australia.

Abstract

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.

PMID:
29979676
PMCID:
PMC6051668
DOI:
10.1371/journal.pgen.1007502
[Indexed for MEDLINE]
Free PMC Article

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