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Biochemical and biomechanical characteristics of dystrophin-deficient mdx3cv mouse lens
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 6.2 ) Pub Date : 2020-10-27 , DOI: 10.1016/j.bbadis.2020.165998
Shruthi Karnam 1 , Nikolai P Skiba 1 , Ponugoti V Rao 2
Affiliation  

The molecular and cellular basis for cataract development in mice lacking dystrophin, a scaffolding protein that links the cytoskeleton to the extracellular matrix, is poorly understood. In this study, we characterized lenses derived from the dystrophin-deficient mdx3cv mouse model. Expression of Dp71, a predominant isoform of dystrophin in the lens, was induced during lens fiber cell differentiation. Dp71 was found to co-distribute with dystroglycan, connexin-50 and 46, aquaporin-0, and NrCAM as a large cluster at the center of long arms of the hexagonal fibers. Although mdx3cv mouse lenses exhibited dramatically reduced levels of Dp71, only older lenses revealed punctate nuclear opacities compared to littermate wild type (WT) lenses. The levels of dystroglycan, syntrophin, and dystrobrevin which comprise the dystrophin-associated protein complex (DAPC), and NrCAM, connexin-50, and aquaporin-0, were significantly lower in the lens membrane fraction of adult mdx3cv mice compared to WT mice. Additionally, decreases were observed in myosin light chain phosphorylation and lens stiffness together with a significant elevation in the levels of utrophin, a functional homolog of dystrophin in mdx3cv mouse lenses compared to WT lenses. The levels of perlecan and laminin (ligands of α-dystroglycan) remained normal in dystrophin-deficient lens fibers. Taken together, although mdx3cv mouse lenses exhibit only minor defects in lens clarity possibly due to a compensatory increase in utrophin, the noted disruptions of DAPC, stability, and organization of membrane integral proteins of fibers, and stiffness of mdx3cv lenses reveal the importance of dystrophin and DAPC in maintaining lens clarity and function.



中文翻译:

抗肌萎缩蛋白缺陷型 mdx3cv 小鼠晶状体的生化和生物力学特征

缺乏肌营养不良蛋白(一种将细胞骨架与细胞外基质连接起来的支架蛋白)小鼠白内障发展的分子和细胞基础尚不清楚。在这项研究中,我们对来自抗肌萎缩蛋白缺陷的mdx 3cv小鼠模型的镜片进行了表征。Dp71 是晶状体中肌营养不良蛋白的主要同种型,在晶状体纤维细胞分化过程中被诱导表达。发现 Dp71 与肌营养不良聚糖、连接蛋白 50 和 46、水通道蛋白 0 和 NrCAM 作为六角形纤维长臂中心的一个大簇共同分布。虽然mdx 3cv小鼠镜片的 Dp71 水平显着降低,与同窝野生型 (WT) 镜片相比,只有较旧的镜片显示点状核混浊。与 WT 小鼠相比,成年mdx 3cv小鼠的晶状体膜部分中的肌营养不良蛋白、肌营养不良蛋白和肌营养不良蛋白复合物 (DAPC) 以及 NrCAM、连接蛋白-50 和水通道蛋白-0 的水平显着降低. 此外,观察到肌球蛋白轻链磷酸化和晶状体硬度降低,同时 utrophin 水平显着升高,utrophin 是mdx 3cv中肌营养不良蛋白的功能同源物鼠标镜头与 WT 镜头相比。在肌营养不良蛋白缺乏的晶状体纤维中,perlecan 和层粘连蛋白(α-肌营养不良聚糖的配体)的水平保持正常。综上所述,虽然mdx 3cv鼠标镜片仅显示出轻微的镜片清晰度缺陷,这可能是由于 utrophin 的补偿性增加,但注意到的 DAPC 破坏、纤维膜整合蛋白的稳定性和组织以及mdx 3cv镜片的刚度揭示了重要性肌营养不良蛋白和 DAPC 在维持晶状体清晰度和功能方面的作用。

更新日期:2020-11-06
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