title: NFATC1 promotes epicardium-derived cell invasion into myocardium.
abstract: Epicardium-derived cells (EPDCs) contribute to formation of coronary vessels and fibrous matrix of the mature heart. Nuclear factor of activated T-cells cytoplasmic 1 (NFATC1) is expressed in cells of the proepicardium (PE), epicardium and EPDCs in mouse and chick embryos. Conditional loss of NFATC1 expression in EPDCs in mice causes embryonic death by E18.5 with reduced coronary vessel and fibrous matrix penetration into myocardium. In osteoclasts, calcineurin-mediated activation of NFATC1 by receptor activator of NFκB ligand (RANKL) signaling induces cathepsin K (CTSK) expression for extracellular matrix degradation and cell invasion. RANKL/NFATC1 pathway components also are expressed in EPDCs, and loss of NFATC1 in EPDCs causes loss of CTSK expression in the myocardial interstitium in vivo. Likewise, RANKL treatment induces Ctsk expression in PE-derived cell cultures via a calcineurin-dependent mechanism. In chicken embryo hearts, RANKL treatment increases the distance of EPDC invasion into myocardium, and this response is calcineurin dependent. Together, these data demonstrate a crucial role for the RANKL/NFATC1 signaling pathway in promoting invasion of EPDCs into the myocardium by induction of extracellular matrix-degrading enzyme gene expression.
authors: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center ML7020, Cincinnati, OH 45229, USA.
authors: Michelle D
authors: MD
authors: Combs
authors: Caitlin M
authors: CM
authors: Braitsch
authors: Alexander W
authors: AW
authors: Lange
authors: Jeanne F
authors: JF
authors: James
authors: Katherine E
authors: KE
authors: Yutzey
mesh_terms: D000818:Animals; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D003331:Coronary Vessels / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D004622:Embryo, Mammalian; D005109:Extracellular Matrix / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010496:Pericardium / Q000166:cytology* / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; D053245:RANK Ligand; D025721:WT1 Proteins; D056657:Cathepsin K