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首页> 外文期刊>American Journal of Physiology >Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.
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Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.

机译：钙调神经磷酸酶-NFAT信号与GABP和过氧化物酶体PGC-1 {α}一起驱动神经肌肉接头处的卵磷脂的基因表达。

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We examined whether calcineurin-NFAT (nuclear factors of activated T cells) signaling plays a role in specifically directing the expression of utrophin in the synaptic compartment of muscle fibers. Immunofluorescence experiments revealed the accumulation of components of the calcineurin-NFAT signaling cascade within the postsynaptic membrane domain of the neuromuscular junction. RT-PCR analysis using synaptic vs. extrasynaptic regions of muscle fibers confirmed these findings by showing an accumulation of calcineurin transcripts within the synaptic compartment. We also examined the effect of calcineurin on utrophin gene expression. Pharmacological inhibition of calcineurin in mice with either cyclosporin A or FK506 resulted in a marked decrease in utrophin A expression at synaptic sites, whereas constitutive activation of calcineurin had the opposite effect. Mutation of the previously identified NFAT binding site in the utrophin A promoter region, followed by direct gene transfer studies in mouse muscle, led to an inhibition in the synaptic expression of a lacZ reporter gene construct. Transfection assays performed with cultured myogenic cells indicated that calcineurin acted additively with GA binding protein (GABP) to transactivate utrophin A gene expression. Because both GABP- and calcineurin-mediated pathways are targeted by peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), we examined whether this coactivator contributes to utrophin gene expression. In vitro and in vivo transfection experiments showed that PGC-1alpha alone induces transcription from the utrophin A promoter. Interestingly, this induction is largely potentiated by coexpression of PGC-1alpha with GABP. Together, these studies indicate that the synaptic expression of utrophin is also driven by calcineurin-NFAT signaling and occurs in conjunction with signaling events that involve GABP and PGC-1alpha.
机译：我们检查了钙调神经磷酸酶-NFAT（活化的T细胞的核因子）信号传导是否在特异性指导肌纤维突触区中的卵磷脂的表达中发挥作用。免疫荧光实验揭示了钙调神经磷酸酶-NFAT信号级联的组分在神经肌肉接头的突触后膜结构域内的积累。使用肌纤维的突触区与突触外区进行RT-PCR分析，通过显示钙调神经磷酸酶转录物在突触区室中的积累，证实了这些发现。我们还检查了钙调神经磷酸酶对促性腺激素基因表达的影响。用环孢菌素A或FK506在小鼠中对钙调神经磷酸酶的药理抑制作用导致突触位点的促性腺激素A表达显着降低，而钙调神经磷酸酶的组成性激活具有相反的作用。突变蛋白的启动子区域中先前确定的NFAT结合位点发生突变，然后在小鼠肌肉中进行直接基因转移研究，导致lacZ报告基因构建物的突触表达受到抑制。用培养的成肌细胞进行的转染分析表明，钙调神经磷酸酶与GA结合蛋白（GABP）发生加和性反应，从而激活卵磷脂A基因表达。因为过氧化物酶体增殖物激活的受体-γ共激活因子-1alpha（PGC-1alpha）靶向了GABP和钙调神经磷酸酶介导的途径，所以我们检查了这种共激活因子是否有助于促卵磷脂的基因表达。体外和体内转染实验表明，单独的PGC-1alpha诱导了来自卵磷脂A启动子的转录。有趣的是，PGC-1α与GABP的共表达大大增强了这种诱导作用。总之，这些研究表明，钙调神经磷酸酶-NFAT信号转导也促进了卵磷脂的突触表达，并与涉及GABP和PGC-1alpha的信号转导事件一起发生。

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