NFATc3 and NFATc4 are required for cardiac development and mitochondrial function.
Activation of the nuclear factor of activated T-cell (NFAT) family of transcription factors is associated with changes in gene expression and myocyte function in adult cardiac and skeletal muscle. However, the role of NFATs in normal embryonic heart development is not well characterized. In this report, the function of NFATc3 and NFATc4 in embryonic heart development was examined in mice with targeted disruption of both nfatc3 and nfatc4 genes. The nfatc3-/-nfatc4-/- mice demonstrate embryonic lethality after embryonic day 10.5 and have thin ventricles, pericardial effusion, and a reduction in ventricular myocyte proliferation. Cardiac mitochondria are swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis are not evident. Furthermore, enzymatic activity of complex II and IV of the respiratory chain and mitochondrial oxidative activity are reduced in nfatc3-/-nfatc4-/- cardiomyocytes. Cardiac-specific expression of constitutively active NFATc4 in nfatc3-/-nfatc4-/- embryos prolongs embryonic viability to embryonic day 12 and preserves ventricular myocyte proliferation, compact zone density, and trabecular formation. The rescued embryos also maintain cardiac mitochondrial ultrastructure and complex II enzyme activity. Together, these data support the hypothesis that loss of NFAT activity in the heart results in a deficiency in mitochondrial energy metabolism required for cardiac morphogenesis and function.
Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center Cincinnati, ML 7020, 3333 Burnet Ave, Cincinnati, Ohio 45229, USA.
Paul B
PB
Bushdid
Hanna
H
Osinska
Ronald R
RR
Waclaw
Jeffery D
JD
Molkentin
Katherine E
KE
Yutzey
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; C467907:Nfatc4 protein, mouse; D014157:Transcription Factors; C445503:transcription factor NF-AT c3; D001973:Bromodeoxyuridine