Essential role of developmentally activated hypoxia-inducible factor 1alpha for cardiac morphogenesis and function.
Development of the mammalian heart is governed by precisely orchestrated interactions between signaling pathways integrating environmental cues and a core cardiac transcriptional network that directs differentiation, growth and morphogenesis. Here we report that in mice, at about embryonic day (E)8.5 to E10.0, cardiac development proceeds in an environment that is hypoxic and characterized by high levels of hypoxia-inducible factor (HIF)1alpha protein. Mice lacking HIF1alpha in ventricular cardiomyocytes exhibit aborted development at looping morphogenesis and embryonic lethality between E11.0 to E12.0. Intriguingly, HIF1alpha-deficient hearts display reduced expression of the core cardiac transcription factors Mef2C and Tbx5 and of titin, a giant protein that serves as a template for the assembly and organization of the sarcomere. Chromatin immunoprecipitation experiments revealed that Mef2C, Tbx5, and titin are direct target genes of HIF1alpha in vivo. Thus, hypoxia signaling controls cardiac development through HIF1alpha-mediated transcriptional regulation of key components of myofibrillogenesis and the cardiac transcription factor network, thereby providing a mechanistic basis of how heart development, morphogenesis, and function is coupled to low oxygen tension during early embryogenesis.
Institute of Cell Biology, Eidgenössische Technische Hochschule, Zürich, Switzerland.
Jaya
J
Krishnan
Preeti
P
Ahuja
Sereina
S
Bodenmann
Don
D
Knapik
Evelyne
E
Perriard
Wilhelm
W
Krek
Jean-Claude
JC
Perriard
D000818:Animals; D064211:Connectin; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006321:Heart / Q000196:embryology*; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics
D064211:Connectin; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D011494:Protein Kinases