Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature.
Vascular development requires an orderly exchange of signals between growing vessels and their supporting tissues, but little is known of the intracellular signaling pathways underlying this communication. We find that mice with disruptions of both NFATc4 and the related NFATc3 genes die around E11 with generalized defects in vessel assembly as well as excessive and disorganized growth of vessels into the neural tube and somites. Since calcineurin is thought to control nuclear localization of NFATc proteins, we introduced a mutation into the calcineurin B gene that prevents phosphatase activation by Ca(2+) signals. These CnB mutant mice exhibit vascular developmental abnormalities similar to the NFATc3/c4 null mice. We show that calcineurin function is transiently required between E7.5 and E8.5. Hence, early calcineurin/NFAT signaling initiates the later cross-talk between vessels and surrounding tissues that pattern the vasculature.
Graef
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IA
Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Chen
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Chen
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Kuo
A
A
Crabtree
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GR
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001808:Blood Vessels / Q000196:embryology* / Q000502:physiology / Q000648:ultrastructure; D019521:Body Patterning; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002490:Central Nervous System / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology; D018390:Gene Targeting; D006321:Heart / Q000196:embryology / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000196:embryology; D050778:NFATC Transcription Factors; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; C494009:Nfatc3 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin; D002118:Calcium