Activation of Type 4 Metabotropic Glutamate Receptor Regulates Proliferation and Neuronal Differentiation in a Cultured Rat Retinal Progenitor Cell Through the Suppression of the cAMP/PTEN/AKT Pathway
Activation of Type 4 Metabotropic Glutamate Receptor Regulates Proliferation and Neuronal Differentiation in a Cultured Rat Retinal Progenitor Cell Through the Suppression of the cAMP/PTEN/AKT Pathway
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4 型代谢型谷氨酸受体的激活通过抑制 cAMP/PTEN/AKT 通路调节培养的大鼠视网膜祖细胞的增殖和神经元分化
DOI：
10.3389/fnmol.2020.00141
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发表时间：
2020-08
影响因子：
4.8
通讯作者：
Zheng Xiaoyan
中科院分区：
文献类型：
--
作者：
Zhang Zhichao;Liu Yingfei;Luan Yan;Zhu Kun;Hu Baoqi;Ma Bo;Chen Li;Liu Xuan;Lu Haixia;Chen Xinlin;Liu Yong;Zheng Xiaoyan
视网膜祖细胞（RPC）在整个生命过程中保留在眼睛中，其特征在于它们的自我更新能力以及它们分化为不同细胞类型的能力。最近的一项研究表明，代谢型谷氨酸受体（mGluRs）参与多种类型干细胞的过程。因此，阐明mGluRs不同亚型在RPCs中的功能，可能为调节视网膜变性后内源性RPCs的增殖和分化提供新的治疗策略。在这项研究中，我们观察到mGluR 4在RPC中功能性表达，对细胞活力和细胞内cAMP浓度有影响。VU 0155041（VU，mGluR 4阳性变构选择性调节剂）激活mGluR 4可减少BrdU+/Pax 6+双阳性细胞数量和细胞周期蛋白D1表达水平，同时增加神经元特异性III类β-微管蛋白（Tuj 1）和双皮质蛋白（DCX）阳性细胞数量。通过靶向特异性siRNA敲低mGluR 4可消除VU对RPC增殖和神经元分化的影响。进一步研究表明，mGluR 4激活抑制AKT磷酸化和上调PTEN蛋白表达。此外，VU 0155041诱导的RPC增殖抑制和神经元分化的增强被Forskolin（腺苷酸环化酶激活剂）和VO-OHpic三水合物（PTEN抑制剂）显著阻碍。相比之下，LY 294002（一种高选择性Akt抑制剂）对增殖和分化的影响与VU相似。这些结果表明，mGluR 4激活可以通过cAMP/PTEN/AKT通路抑制培养的大鼠RPCs的增殖并促进其神经分化。我们的研究为进一步的药理学工作奠定了基础，为多种视网膜疾病探索一种新的潜在治疗方法。
Retinal progenitor cells (RPCs) remain in the eye throughout life and can be characterized by their ability for self-renewal as well as their specialization into different cell types. A recent study has suggested that metabotropic glutamate receptors (mGluRs) participate in the processes of multiple types of stem cells. Therefore, clarifying the functions of different subtypes of mGluRs in RPCs may provide a novel treatment strategy for regulating the proliferation and differentiation of endogenous RPCs after retinal degeneration. In this study, we observed that mGluR4 was functionally expressed in RPCs, with an effect on cell viability and intracellular cAMP concentration. The activation of mGluR4 by VU0155041 (VU, mGluR4 positive allosteric selective modulator) reduced the number of BrdU+/Pax6+ double-positive cells and Cyclin D1 expression levels while increasing the number of neuron-specific class III beta-tubulin (Tuj1)- and Doublecortin (DCX)-positive cells. The knockdown of mGluR4 by target-specific siRNA abolished the effects of VU on RPC proliferation and neuronal differentiation. Further investigation demonstrated that mGluR4 activation inhibited AKT phosphorylation and up-regulated PTEN protein expression. Moreover, the VU0155041-induced inhibition of proliferation and enhancement of neuronal differentiation in RPCs were significantly hampered by Forskolin (adenylyl cyclase activator) and VO-OHpic trihydrate (PTEN inhibitor). In contrast, the effect of LY294002 (a highly selective Akt inhibitor) on proliferation and differentiation was similar to that of VU. These results indicate that mGluR4 activation can suppress proliferation and promote the neural differentiation of cultured rat RPCs through the cAMP/PTEN/AKT pathway. Our research lays the foundation for further pharmacological work exploring a novel potential therapy for several retinal diseases.
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影响因子：
9.2
作者：
Mate Naszai;Julia B. Cordero
通讯作者：
Mate Naszai;Julia B. Cordero
影响因子：
3
作者：
Wendl MC
通讯作者：
Wendl MC
DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
影响因子：
3.3
作者：
Lingyu Zhao;Q. Jiao;Peng-bo Yang;Xi Chen;Jianshui Zhang;B. Zhao;Peng Zheng;Y. Liu
通讯作者：
Lingyu Zhao;Q. Jiao;Peng-bo Yang;Xi Chen;Jianshui Zhang;B. Zhao;Peng Zheng;Y. Liu
DOI：
10.1016/b978-0-12-820472-6.00057-8
发表时间：
2021
期刊：
Reference Module in Biomedical Sciences
影响因子：
--
作者：
D. Doller
通讯作者：
D. Doller