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鞘氨醇激酶 1 对于维持衰老视网膜的外部/外节膜和相关黏附连接是必需的。

Sphingosine Kinase-1 Is Essential for Maintaining External/Outer Limiting Membrane and Associated Adherens Junctions in the Aging Retina.

机构信息

Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Dean A. McGee Eye Institute, Oklahoma City, OK, 73104, USA.

出版信息

Mol Neurobiol. 2019 Oct;56(10):7188-7207. doi: 10.1007/s12035-019-1599-x. Epub 2019 Apr 17.

DOI:10.1007/s12035-019-1599-x
PMID:30997640
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7425817/
Abstract

Sphingosine-1-phosphate (S1P) produced by sphingosine kinases (SPHK1 and SPHK2) is a signaling molecule involved in cell proliferation and formation of cellular junctions. In this study, we characterized the retinas of Sphk1 knockout (KO) mice by electron microscopy and immunocytochemistry. We also tested cultured Müller glia for their response to S1P. We found that S1P plays an important role in retinal and retinal pigment epithelial (RPE) structural integrity in aging mice. Ultrastructural analysis of Sphk1 KO mouse retinas aged to 15 months or raised with moderate light stress revealed a degenerated outer limiting membrane (OLM). This membrane is formed by adherens junctions between neighboring Müller glia and photoreceptor cells. We also show that Sphk1 KO mice have reduced retinal function in mice raised with moderate light stress. In vitro assays revealed that exogenous S1P modulated cytoskeletal rearrangement and increased N-cadherin production in human Müller glia cells. Aged mice also had morphological degeneration of the RPE, as well as increased lipid storage vacuoles and undigested phagosomes reminiscent of RPE in age-related macular degeneration. These findings show that SPHK1 and S1P play a vital role in the structural maintenance of the mammalian retina and retinal pigmented epithelium by supporting the formation of adherens junctions.

摘要

鞘氨醇-1-磷酸（S1P）由鞘氨醇激酶（SPHK1 和 SPHK2）产生，是一种参与细胞增殖和细胞连接形成的信号分子。在这项研究中，我们通过电子显微镜和免疫细胞化学对 Sphk1 敲除（KO）小鼠的视网膜进行了特征描述。我们还测试了培养的 Müller 胶质细胞对 S1P 的反应。我们发现 S1P 在衰老小鼠的视网膜和视网膜色素上皮（RPE）结构完整性中发挥重要作用。对 15 个月大的 Sphk1 KO 鼠视网膜进行超微结构分析或在中度光应激下培养，发现已退化的外界膜（OLM）。该膜由相邻 Müller 胶质细胞和光感受器细胞之间的黏附连接形成。我们还表明，在中度光应激下饲养的 Sphk1 KO 小鼠的视网膜功能降低。体外实验表明，外源性 S1P 可调节人 Müller 胶质细胞的细胞骨架重排并增加 N-钙黏蛋白的产生。衰老的小鼠还表现出 RPE 的形态退化，以及更多的脂滴储存空泡和未消化的吞噬体，类似于年龄相关性黄斑变性的 RPE。这些发现表明，SPHK1 和 S1P 通过支持黏附连接的形成，在维持哺乳动物视网膜和视网膜色素上皮的结构中发挥重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/9b02c4c01d43/nihms-1527288-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/f3512b3a06f7/nihms-1527288-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/9b02c4c01d43/nihms-1527288-f0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/9e62db99d7af/nihms-1527288-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/f8a5d16fb92b/nihms-1527288-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/02138645e130/nihms-1527288-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/9ee38a55ad17/nihms-1527288-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/95bc740c0ba2/nihms-1527288-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/108c6795f57a/nihms-1527288-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e19d/7425817/9b02c4c01d43/nihms-1527288-f0009.jpg

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