Yes 相关蛋白通过 β-catenin 信号促进星形胶质细胞中兴奋性氨基酸转运体 2 的表达来调节谷氨酸稳态,Glia

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Yes 相关蛋白通过 β-catenin 信号促进星形胶质细胞中兴奋性氨基酸转运体 2 的表达来调节谷氨酸稳态
Glia ( IF 5.4 ) Pub Date : 2023-01-08 , DOI: 10.1002/glia.24332
Xingxing Xu ₁ , Jiaojiao Wang ₁ , Siyu Du ₂ , Xiya Shen ₁ , Jiashu Lian ₃ , Jian Zhou ₃ , Mianxian Wang ₁ , Wenjin Feng ₄ , Zhaoting Lv ₂ , Junzhe Zhu ₅ , Lingting Jin ₁ , Huankun Sun ₂ , Lihao Wu ₅ , Xiaoning Wang ₅ , Haoyu Qiu ₅ , Wei Wang ₂ , Honglin Teng ₃ , Ying Wang ₆ , Zhihui Huang _{1,

3,

7}

Affiliation

谷氨酸的稳态主要受兴奋性氨基酸转运蛋白 (EAAT) 调节，尤其是星形胶质细胞中的 EAAT2。由 EAAT2 功能障碍或失调引起的突触间隙谷氨酸过多可导致兴奋性毒性、神经元死亡和认知功能障碍。然而，星形胶质细胞EAAT2表达和功能的详细调控机制尚不清楚。^{在这项研究中，首先，我们发现 YAP GFAP} -CKO 小鼠（有条件地敲除星形胶质细胞中的 Yes 相关蛋白 [YAP]）的神经元死亡和认知功能受损增加，并通过 RNA 测序将 EAAT2 鉴定为 YAP 的下游靶标。^{其次，EAAT2 的表达在培养的 YAP -/-星形胶质细胞和 YAP}^GFAP海马体中降低^{-CKO 小鼠，谷氨酸摄取在 YAP -/-}星形胶质细胞中减少，但在 YAP 上调的星形胶质细胞中增加。^{第三，对该机制的进一步研究表明，β-连环蛋白的 mRNA 和蛋白质水平在 YAP -/-}星形胶质细胞中降低，而在 YAP 上调的星形胶质细胞中增加。Wnt3a 激活 YAP 信号并通过 β-连环蛋白上调 EAAT2。此外，β-连环蛋白的过表达或激活部分恢复了 EAAT2 的下调、谷氨酸摄取的损害、神经元死亡和由 YAP 缺失引起的认知能力下降。最后，EAAT2 的激活还挽救了 YAP ^{GFAP中的神经元死亡和认知能力下降}-CKO小鼠。综上所述，我们的研究确定了 YAP 信号在星形胶质细胞中通过 β-连环蛋白/EAAT2 通路调节谷氨酸稳态中未被认识的作用，这可能为与 EAAT2 功能障碍或失调密切相关的脑部疾病的发病机制提供新的见解，促进临床策略的发展。

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Yes-associated protein regulates glutamate homeostasis through promoting the expression of excitatory amino acid transporter-2 in astrocytes via β-catenin signaling

The homeostasis of glutamate is mainly regulated by the excitatory amino acid transporters (EAATs), especially by EAAT2 in astrocytes. Excessive glutamate in the synaptic cleft caused by dysfunction or dysregulation of EAAT2 can lead to excitotoxicity, neuronal death and cognitive dysfunction. However, it remains unclear about the detailed regulation mechanism of expression and function of astrocytic EAAT2. In this study, first, we found increased neuronal death and impairment of cognitive function in YAP^GFAP-CKO mice (conditionally knock out Yes-associated protein [YAP] in astrocytes), and identified EAAT2 as a downstream target of YAP through RNA sequencing. Second, the expression of EAAT2 was decreased in cultured YAP^−/− astrocytes and the hippocampus of YAP^GFAP-CKO mice, and glutamate uptake was reduced in YAP^−/− astrocytes, but increased in YAP-upregulated astrocytes. Third, further investigation of the mechanism showed that the mRNA and protein levels of β-catenin were decreased in YAP^−/− astrocytes and increased in YAP-upregulated astrocytes. Wnt3a activated YAP signaling and up-regulated EAAT2 through β-catenin. Furthermore, over-expression or activation of β-catenin partially restored the downregulation of EAAT2, the impairment of glutamate uptake, neuronal death and cognitive decline that caused by YAP deletion. Finally, activation of EAAT2 also rescued neuronal death and cognitive decline in YAP^GFAP-CKO mice. Taken together, our study identifies an unrecognized role of YAP signaling in the regulation of glutamate homeostasis through the β-catenin/EAAT2 pathway in astrocytes, which may provide novel insights into the pathogenesis of brain diseases that closely related to the dysfunction or dysregulation of EAAT2, and promote the development of clinical strategy.

更新日期：2023-01-08

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