Biochemical and biomechanical characteristics of dystrophin-deficient mdx(3cv) mouse lens.
Biochemical and biomechanical characteristics of dystrophin-deficient mdx(3cv) mouse lens.
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DOI：
10.1016/j.bbadis.2020.165998
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发表时间：
2021-01-01
期刊：
影响因子：
--
通讯作者：
Rao PV
中科院分区：
文献类型：
--
作者：
Karnam S;Skiba NP;Rao PV
缺乏dystrophin的小鼠白内障发生的分子和细胞基础尚不清楚。dystrophin是一种连接细胞骨架和细胞外基质的支架蛋白。在这项研究中，我们对来自dystrophin缺乏症mdx3cv小鼠模型的晶状体进行了表征。Dp71是晶状体中主要的抗肌营养不良蛋白亚型，在晶状体纤维细胞分化过程中被诱导表达。Dp71与营养不良聚糖、连接蛋白-50和46、水通道蛋白-0和NrCAM共同分布在六角形纤维长臂中心。尽管mdx3cv小鼠晶状体的Dp71水平显著降低，但只有较老的晶状体与斜生野生型(WT)晶状体相比，显示出点状核不透明。在成年mdx3cv小鼠的晶状体膜组分中，组成dystrophin相关蛋白复合体(DAPC)和NrCAM、连接蛋白-50和水通道蛋白-0的抗肌营养不良蛋白、合体营养素和抗肌营养不良蛋白的水平显著低于wt小鼠。此外，与WT晶状体相比，mdx3cv小鼠晶状体中肌球蛋白轻链磷酸化水平和晶状体硬度降低，同时utroin水平显著升高，utroin是dystrophin的功能同源物。在dystrophin缺乏的晶状体纤维中，Perlecan和Laminin(α-dystroglan的配体)的水平保持正常。综上所述，尽管mdx3cv小鼠晶状体的清晰度仅有轻微缺陷，可能是由于促性腺激素代偿性增加所致，但ddx3cv晶状体的DAPC、纤维膜整体蛋白的稳定性和组织以及晶状体僵硬的显著破坏揭示了dystrophin和DAPC在维持晶状体清晰度和功能方面的重要性。
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.
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