Storm Tina, Heegaard Steffen, Christensen Erik I, Nielsen Rikke
Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Wilhelm Meyers Allé 3, DK-8000, Aarhus, Denmark,
Cell Tissue Res. 2014 Oct;358(1):99-107. doi: 10.1007/s00441-014-1919-4. Epub 2014 Jul 1.
In man, mutations of the megalin-encoding gene causes the rare Donnai-Barrow/Facio-Oculo-Acoustico-Renal Syndrome, which is partially characterized by high-grade myopia. Previous studies of renal megalin function have established that megalin is crucial for conservation of renal filtered nutrients including vitamin A; however, the role of megalin in ocular physiology and development is presently unknown. Therefore, we investigate ocular megalin expression and the ocular phenotype of megalin-deficient mice. Topographical and subcellular localization of megalin as well as the ocular phenotype of megalin-deficient mice were examined with immunological techniques using light, confocal and electron microscopy. We identified megalin in the retinal pigment epithelium (RPE) and non-pigmented ciliary body epithelium (NPCBE) in normal mouse eyes. Immunocytochemical investigations furthermore showed that megalin localizes to vesicular structures in the RPE and NPCBE cells. Histological investigations of ocular mouse tissue also identified a severe myopia phenotype as well as enlarged RPE melanosomes and abnormal ciliary body development in the megalin-deficient mice. In conclusion, the complex ocular phenotype observed in the megalin-deficient mice suggests that megalin-mediated developmental abnormalities may contribute to the high myopia phenotype observed in the Donnai-Barrow Syndrome patients and, thus, that megalin harbors important roles in ocular development and physiology. Finally, our data show that megalin-deficient mice may provide a valuable model for future studies of megalin in ocular physiology and pathology.
在人类中，编码巨蛋白的基因突变会导致罕见的多纳伊 - 巴罗综合征/面 - 眼 - 耳 - 肾综合征，其部分特征为高度近视。先前关于肾脏巨蛋白功能的研究已证实，巨蛋白对于保留包括维生素A在内的经肾脏滤过的营养物质至关重要；然而，巨蛋白在眼部生理和发育中的作用目前尚不清楚。因此，我们研究了巨蛋白缺陷小鼠的眼部巨蛋白表达及眼部表型。使用光学、共聚焦和电子显微镜的免疫技术检测了巨蛋白的拓扑和亚细胞定位以及巨蛋白缺陷小鼠的眼部表型。我们在正常小鼠眼睛的视网膜色素上皮（RPE）和无色素睫状体上皮（NPCBE）中鉴定出了巨蛋白。免疫细胞化学研究还表明，巨蛋白定位于RPE和NPCBE细胞中的囊泡结构。对小鼠眼部组织的组织学研究还在巨蛋白缺陷小鼠中发现了严重的近视表型以及RPE黑素体增大和睫状体发育异常。总之，在巨蛋白缺陷小鼠中观察到的复杂眼部表型表明，巨蛋白介导的发育异常可能导致多纳伊 - 巴罗综合征患者中观察到的高度近视表型，因此，巨蛋白在眼部发育和生理中具有重要作用。最后，我们的数据表明，巨蛋白缺陷小鼠可能为未来研究巨蛋白在眼部生理和病理中的作用提供有价值的模型。
