Repressor element 1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcription repressor and its expression is regulated by the Wnt pathway through β-catenin. Metabotropic glutamate receptor 5 (mGluR5) signaling plays a key role in controlling neuronal gene expression. Interestingly, REST/NRSF nuclear translocation and signaling, as well as mGluR5 signaling are altered in the presence of mutant huntingtin. It remains unclear whether mGluR5 can modulate Wnt and REST/NRSF signaling under physiological conditions and whether this modulation is altered in Huntington’s disease (HD). Using primary corticostriatal neurons derived from wild type mouse embryos, we find that targeting mGluR5 using the agonist, DHPG, or the negative allosteric modulator, CTEP, modulates REST/NRSF expression by regulating the assembly of N-cadherin/ β-catenin complex in a Src kinase-dependent manner. We have validated our in vitro findings in vivo using two HD mouse models. Specifically, we show that pharmacological inhibition of mGluR5 in zQ175 mice and genetic ablation of mGluR5 in BACHD mice corrected the pathological activation of Src and rescued REST/NRSF-dependent signaling. Together, our data provide evidence that mGluR5 regulates REST/NRSF expression via the Wnt pathway and highlight the contribution of impaired REST/ NRSF signaling to HD pathology.

中文翻译：

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mGluR5 通过 N-钙粘蛋白/β-连环蛋白复合物调节亨廷顿病中的 REST/NRSF 信号传导。

阻遏元件1-沉默转录因子/神经元限制性沉默因子（REST/NRSF）是一种转录阻遏因子，其表达通过β-连环蛋白受Wnt途径调节。代谢型谷氨酸受体 5 (mGluR5) 信号在控制神经元基因表达中发挥关键作用。有趣的是，REST/NRSF 核易位和信号传导以及 mGluR5 信号传导在突变亨廷顿蛋白的存在下发生改变。目前尚不清楚 mGluR5 是否可以在生理条件下调节 Wnt 和 REST/NRSF 信号传导，以及这种调节是否在亨廷顿病 (HD) 中发生改变。使用源自野生型小鼠胚胎的原代皮质纹状体神经元，我们发现使用激动剂 DHPG 或负变构调节剂 CTEP 靶向 mGluR5，通过调节 N-钙粘蛋白/β-连环蛋白复合物的组装来调节 REST/NRSF 表达。 Src激酶依赖性方式。我们使用两种 HD 小鼠模型在体内验证了我们的体外研究结果。具体来说，我们表明，zQ175 小鼠中 mGluR5 的药理抑制和 BACHD 小鼠中 mGluR5 的基因消除纠正了 Src 的病理激活，并挽救了 REST/NRSF 依赖性信号传导。总之，我们的数据提供了 mGluR5 通过 Wnt 通路调节 REST/NRSF 表达的证据，并强调了 REST/NRSF 信号传导受损对 HD 病理学的影响。