Yasumuro Hirofumi, Sakurai Keisuke, Toyama Fubito, Maruo Fumiaki, Chiba Chikafumi
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba 305-8572, Japan.
Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba 305-8572, Japan.
Biomedicines. 2017 May 20;5(2):25. doi: 10.3390/biomedicines5020025.
The newt is an amazing four-limbed vertebrate that can regenerate various body parts including the retina. In this animal, when the neural retina (NR) is removed from the eye by surgery (retinectomy), both the NR and the retinal pigment epithelium (RPE) eventually regenerate through the process of reprogramming and proliferation of RPE cells. Thus far, we have pursued the onset mechanism of adult newt retinal regeneration. In this study, using an in vitro system, we found that both mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK and β-catenin were involved in cell cycle re-entry of RPE cells. MEK-ERK signaling activity in RPE cells was strengthened by retinectomy, and nuclear translocation of β-catenin in RPE cells was induced by attenuation of cell-cell contact, which was promoted by incision of the RPE or its treatment with ethylene glycol tetraacetic acid (EGTA). EGTA is a Ca chelator that disrupts cadherin-mediated cell-cell adhesion. Reinforcement of MEK-ERK signaling activity was a prerequisite for nuclear translocation of β-catenin. These results suggest that retinectomy followed by attenuation of cell-cell contact may trigger cell cycle re-entry of RPE cells. This study, together with our previous findings concerning the proliferation and multipotency of adult newt RPE cells, provides insight into the mechanism of the multi-step trigger in which the onset of retinal regeneration in the adult newt is rigorously controlled.
蝾螈是一种令人惊奇的四足脊椎动物，能够再生包括视网膜在内的各种身体部位。在这种动物中，当通过手术将神经视网膜（NR）从眼睛中移除（视网膜切除术）时，NR和视网膜色素上皮（RPE）最终都会通过RPE细胞的重编程和增殖过程而再生。到目前为止，我们一直在探究成年蝾螈视网膜再生的起始机制。在本研究中，我们使用体外系统发现，丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）激酶（MEK）-ERK和β-连环蛋白都参与了RPE细胞的细胞周期重新进入。视网膜切除术增强了RPE细胞中的MEK-ERK信号活性，而RPE细胞中细胞间接触的减弱诱导了β-连环蛋白的核转位，RPE的切割或用乙二醇四乙酸（EGTA）处理可促进这种减弱。EGTA是一种钙螯合剂，会破坏钙黏蛋白介导的细胞间黏附。MEK-ERK信号活性的增强是β-连环蛋白核转位的先决条件。这些结果表明，视网膜切除术后细胞间接触的减弱可能触发RPE细胞的细胞周期重新进入。本研究与我们之前关于成年蝾螈RPE细胞增殖和多能性的发现一起，为成年蝾螈视网膜再生起始受到严格控制的多步骤触发机制提供了见解。
