Key result
NFATc1 promotes a sequential pattern of gene expression during heart valve development via cooperation with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2.
NFATc1 promotes a sequential pattern of gene expression during heart valve development by cooperating with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2.
May inform congenital valve disease models; leaves open therapeutic targeting of NFATc1 pathways in humans.
RATIONALE: NFATc1 (nuclear factor of activated T-cells cytoplasmic 1) activity in endocardial cushion (ECC) endothelial cells is required for normal ECC growth and extracellular matrix (ECM) remodeling during heart valve development. OBJECTIVE: The mechanisms of NFATc1 activation and downstream effects on cell proliferation and ECM-remodeling enzyme gene expression were examined in NFATc1 mutant mice and chick ECC explants. METHODS AND RESULTS: NFATc1(-/-) mice display reduced proliferation of ECC endothelial and mesenchymal cells at embryonic day 10.5, whereas myocardial cells are unaffected. Vascular endothelial growth factor A (VEGF) activates NFATc1 and promotes ECC cell proliferation via the regulatory phosphatase, calcineurin, and mitogen-activated protein kinase-extracellular signal-regulated kinase 1-extracellular signal-regulated kinase 1/2 (MEK1-ERK1/2)-dependent signaling. As ECCs mature, RANKL (receptor activator of nuclear factor kappaB ligand) and the ECM-remodeling enzyme cathepsin K (CtsK) are expressed by ECC endothelial cells. RANKL inhibits VEGF-induced cell proliferation while causing increased expression of CtsK via calcineurin/NFATc1 and c-Jun N-terminal kinase (JNK)1/2-dependent signaling. CONCLUSION: These data support a novel mechanism for the transition from ECC growth to remodeling in which NFATc1 promotes a sequential pattern of gene expression via cooperation with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2.
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Combs et al. (2009) studied Heart valve development. NFATc1 mutation, VEGF, and RANKL vs. Wild-type / untreated controls was evaluated on Cell proliferation and ECM-remodeling enzyme gene expression. NFATc1 promotes a sequential pattern of gene expression during heart valve development via cooperation with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2.
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