Disease relevance of Nfatc1

• These defects lead to embryonic death at E14.5 and are similar to those observed in other mouse models of congenital heart disease, including Sox4 and Nfatc1 null embryos [1].
• We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome [2].
• Calcineurin/NFATc signaling in osteoblasts controls the expression of chemoattractants that attract monocytic osteoclast precursors, thereby coupling bone formation and bone resorption [3].
• Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis [4].
• Here we report that mice with a targeted disruption of the NF-ATc gene show an unexpected and dramatic defect in cardiac morphogenesis, with selective absence of the aortic and pulmonary valves, leading to death in utero from congestive heart failure at days 13.5-17.5 of gestation [5].

High impact information on Nfatc1

• This phenotype is associated with an elevated level of ras signaling in Nf1(-/-) endothelial cells and greater nuclear localization of the transcription factor Nfatc1 [6].
• 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 [7].
• Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts [8].
• Thus, IGF-1 induces calcineurin-mediated signalling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs [9].
• We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway [10].

Biological context of Nfatc1

• In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts [8].
• Characterization of Nfatc1 regulation identifies an enhancer required for gene expression that is specific to pro-valve endocardial cells in the developing heart [11].
• Thus, autoregulation of Nfatc1 is required for maintaining high Nfatc1 expression in pro-valve endocardial cells, while suppression through the Hox site prevents its expression outside pro-valve endocardial cells during valve development [11].
• Our data demonstrate the first autonomous cell-specific enhancer for pro-valve endocardial cells and delineate a unique transcriptional mechanism that regulates endocardial Nfatc1 expression within developing cardiac valves [11].
• Interestingly, expression of Sox4 in the outflow tract and cushions of Foxp1 null embryos is significantly reduced, while remodeling of the cushions is disrupted, as demonstrated by reduced apoptosis and persistent Nfatc1 expression in the cushion mesenchyme [1].

Anatomical context of Nfatc1

• Nfatc1 is an endocardial transcription factor required for development of cardiac valves [11].
• This study suggests that pre-existing NFATc2 contributes to the subsequent induction of Nfatc1 during T cell activation [12].
• Microarray analysis revealed that Nfatc1, another key regulator of osteoclastogenesis, was down-regulated in Fos(-/-) osteoclast precursors [13].
• Of great surprise is the function of Cx45 in the endothelium, where it is essential for synchronized activation of the transcription factor Nfatc1 [14].
• By using RAG-2-deficient blastocyst complementation, we now demonstrate that young, highly chimeric mice lacking NF-ATc have impaired repopulation of both thymus and peripheral lymphoid organs [15].

Associations of Nfatc1 with chemical compounds

• However, we demonstrate that the constitutive nuclear ARE-associated factors react with Abs, raised to NF-ATp and NF-ATc, preferentially bind to the ARE but not to the NF-AT binding site and are cyclosporin A sensitive [16].
• Pharmacologic inhibitors Gö6976 and rottlerin demonstrate that both conventional and novel protein kinase C (PKC) family members regulate endogenous mast cell NFAT activity, and NFAT2 TA [17].
• A high cell density appeared to cause a change in the composition of the culture medium accompanying downregulation of NFAT2 expression, and we identified L-serine (LSer) as essential for the expression of NFAT2 induced by RANKL [18].
• We therefore examined the role of NFATc1 in human beta(3) integrin expression in osteoclast differentiation [19].
• Green fluorescence protein (GFP) or FLAG fusion proteins of either wild-type or constitutively active mutant NFATc [NFATc(S-->A)] were expressed in cultured adult mouse skeletal muscle fibers from flexor digitorum brevis (predominantly fast-twitch) [20].

Regulatory relationships of Nfatc1

• In addition, the nuclear translocation of NFATc1 in the endocardial endothelial cells is inhibited in the Nkx2-5-/- embryos [21].
• Interestingly, IL-4 potently inhibited RANKL-induced expression of NFATc1 at mRNA level [22].
• Expression of NFAT2 increased the expression of IL-4 in both NKT cells and conventional T cells, and NFAT2 activated IL-10 in conventional T cells but not in NKT cells [23].
• These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D [24].
• Lowering extracellular pH dramatically increased accumulation of NFATc1 in nuclei of rat and rabbit osteoclasts to levels comparable with those induced by the proresorptive cytokine receptor activator of NF-kappaB ligand (RANKL) [25].

Other interactions of Nfatc1

• Dysregulation of connexins and inactivation of NFATc1 in the cardiovascular system of Nkx2-5 null mutants [21].
• The aim of this study was to clarify the role of IL-4 on the intracellular signaling of NFATc1 [22].
• In addition, the gene expression of NFATc1 and c-Fos was determined by reverse transcription and polymerase chain reaction [22].
• We propose that one mechanism by which CD4+ NKT cells express IL-4 independent of Stat6 is via increased NFAT2 activity [23].
• However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-gamma promoter counteracted [26].

Analytical, diagnostic and therapeutic context of Nfatc1

• Electrophoresis mobility shift and chromatin immunoprecipitation assays demonstrated binding of Nfatc1 to the Nfat sites, and inactivation of Nfatc1 downregulated the enhancer activity in pro-valve endocardial cells [11].
• The protein expression of IL-4 receptor, NFATc1, and c-Fos was determined by Western blot analysis [22].
• By analyzing a chromosome 18 radiation hybrid panel, the human NFATc gene was localized to the q terminus, closely linked to STS marker D18S497 [27].
• Sequence analysis of the mouse MMP-9 gene promoter region further identified the presence of binding motif (-1123 bp to -1153 bp) for the nuclear factor of activated T cells 1 (NFATc1) transcription factor [28].
• Molecular cloning and functional characterization of murine cDNA encoding transcription factor NFATc [29].

References