Journal
DEVELOPMENTAL DYNAMICS
Volume 237, Issue 12, Pages 3809-3819Publisher
WILEY
DOI: 10.1002/dvdy.21803
Keywords
Nkx2.5; Mef2c; heart development; ventricle; mouse
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Funding
- NIH [RO1HL061677-09 (A.B.F.), NCI T32CA111198 (J.W.V.), 1PO1HL085098-OlAl]
- NATIONAL CANCER INSTITUTE [T32CA111198] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL085098, R01HL061677] Funding Source: NIH RePORTER
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The interactions of diverse transcription factors mediate the molecular programs that regulate mammalian heart development. Among these, Nkx2.5 and the Mef2c regulate common downstream targets and exhibit striking phenotypic similarities when disrupted, suggesting a potential interaction during heart development. Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c. Assessment, of mRNA expression verified spatiotemporal cardiac coexpression. Finally, genetic interaction studies employing histological and molecular analyses showed that, although Nkx2.5(-/-) and Mef2c(-/-) individual mutants both have identifiable ventricles, Nkx2.5(-/-);Mef2c(-/-) double mutants do not, and that mutant cardiomyocytes express only atrial and second heart field markers. Molecular marker and cell death and proliferation analyses provide evidence that ventricular hypoplasia is the result of defective ventricular cell differentiation. Collectively, these data support a hypothesis where physical, functional, and genetic interactions between Nkx2.5 and Mef2c are necessary for ventricle formation. Developmental Dynamics 237:3809-3819, 2008. (c) 2008 Wiley-Liss, Inc.
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