The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice.
The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice.
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DOI：
10.1371/journal.pone.0015730
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发表时间：
2010-12-30
期刊：
影响因子：
3.7
通讯作者：
Ali RR
中科院分区：
文献类型：
--
作者：
Georgiadis A;Tschernutter M;Bainbridge JW;Balaggan KS;Mowat F;West EL;Munro PM;Thrasher AJ;Matter K;Balda MS;Ali RR
细胞-细胞粘附通过提供机械支持和引导细胞增殖和分化来调节上皮的发育和功能。在培养的上皮细胞中，紧密连接蛋白（TJ） ZO -1通过抑制Y-box转录因子ZONAB的活性来调节细胞增殖和基因表达。我们通过慢病毒介导的ZONAB过表达和ZONAB细胞抑制剂ZO-1的敲低，研究了tj相关信号通路在视网膜色素上皮（RPE）中的作用。ZONAB过表达或ZO-1敲低均可导致RPE增殖增加，并诱导上皮-间质转化（EMT）样表型的超微结构改变。电镜分析显示，转导的RPE单层结构紊乱，固缩和单层断裂增加，这与几种EMT标记物的表达增加有关。此外，荧光素血管造影分析表明，ZONAB过表达或ZO-1下调诱导的增殖增加和emt样表型导致RPE功能障碍。这些发现表明，ZO-1和ZONAB对RPE单层的分化和稳态至关重要，并可能参与RPE疾病，如增殖性玻璃体视网膜病变和萎缩性年龄相关性黄斑变性。
Cell-cell adhesion regulates the development and function of epithelia by providing mechanical support and by guiding cell proliferation and differentiation. The tight junction (TJ) protein zonula occludens (ZO)-1 regulates cell proliferation and gene expression by inhibiting the activity of the Y-box transcription factor ZONAB in cultured epithelial cells. We investigated the role of this TJ-associated signalling pathway in the retinal pigment epithelium (RPE) in vivo by lentivirally-mediated overexpression of ZONAB, and knockdown of its cellular inhibitor ZO-1. Both overexpression of ZONAB or knockdown of ZO-1 resulted in increased RPE proliferation, and induced ultrastructural changes of an epithelial-mesenchymal transition (EMT)-like phenotype. Electron microscopy analysis revealed that transduced RPE monolayers were disorganised with increased pyknosis and monolayer breaks, correlating with increased expression of several EMT markers. Moreover, fluorescein angiography analysis demonstrated that the increased proliferation and EMT-like phenotype induced by overexpression of ZONAB or downregulation of ZO-1 resulted in RPE dysfunction. These findings demonstrate that ZO-1 and ZONAB are critical for differentiation and homeostasis of the RPE monolayer and may be involved in RPE disorders such as proliferative vitroretinopathy and atrophic age-related macular degeneration.
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