Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

RATIONALE:Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused cont...

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Bibliographic Details
Published in:Circulation research 2014-03, Vol.114 (7), p.1103-1113
Main Authors: Nakashima, Yasuhiro, Yanez, Diana A, Touma, Marlin, Nakano, Haruko, Jaroszewicz, Artur, Jordan, Maria C, Pellegrini, Matteo, Roos, Kenneth P, Nakano, Atsushi
Format: Article
Language:English
Subjects:
Animals
Cell Proliferation
Heart Atria - cytology
Heart Atria - metabolism
Heart Conduction System - cytology
Heart Conduction System - metabolism
Homeobox Protein Nkx-2.5
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Mice
Mice, Inbred C57BL
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - physiology
Receptors, Notch - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptome
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Summary:RATIONALE:Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart. Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation. OBJECTIVE:In this study, we circumvented these limitations by atrial-restricted deletion of Nkx2-5. METHOD AND RESULTS:Atrial-specific Nkx2-5 mutants died shortly after birth with hyperplastic working myocytes and conduction system including two nodes and internodal tracts. Multicolor reporter analysis revealed that Nkx2-5–null cardiomyocytes displayed clonal proliferative activity throughout the atria, indicating the suppressive role of Nkx2-5 in cardiomyocyte proliferation after chamber ballooning stages. Transcriptome analysis revealed that aberrant activation of Notch signaling underlies hyperproliferation of mutant cardiomyocytes, and forced activation of Notch signaling recapitulates hyperproliferation of working myocytes but not the conduction system. CONCLUSIONS:Collectively, these data suggest that Nkx2-5 regulates the proliferation of atrial working and conduction myocardium in coordination with Notch pathway.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.114.303219