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| Status |
Public on Apr 18, 2018 |
| Title |
Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. The developmental origins and mechanistic basis of varying severity of this pathology are unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis. 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 a marker 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.
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| Overall design |
Fifty mice were assigned to three groups: Nkx2-5Δtrab mice received tamoxifen injections at embryonic stages (E10.5 and E11.5), Nkx2-5Δcomp mice received tamoxifen injections at fetal stages (E13.5 and E14.5), and control mice without tamoxifen injection. For transcriptomic analyse, n=4 per group at 6 month-old mutant mice.
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| Web link |
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007502
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| Contributor(s) |
Choquet C, Nguyen T, Sicard P, Buttigieg E, Tran T, Kober F, Varlet I, Costa MW, Harvey RP, Nguyen C, Rihet P, Richard S, Bernard M, Kelly RG, Lalevée N, Miquerol L |
| Citation(s) |
29979676 |
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| Submission date |
Apr 17, 2018 |
| Last update date |
Jul 19, 2018 |
| Contact name |
Thom Thi Tran |
| E-mail(s) |
thi-thom.tran@inserm.fr
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| Phone |
33(0)491 82 87 25
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| Organization name |
INSERM
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| Department |
Marseille
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| Lab |
TAGC UMR1090
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| Street address |
163, avenue de Luminy
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| City |
Marseille |
| ZIP/Postal code |
13009 |
| Country |
France |
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| Platforms (1) |
| GPL13912 |
Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Feature Number version) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA450553 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE113251_RAW.tar |
152.0 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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