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缝隙连接蛋白 50-R205G 突变干扰晶状体上皮细胞增殖和分化。

Connexin 50-R205G Mutation Perturbs Lens Epithelial Cell Proliferation and Differentiation.

机构信息

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出版信息

Invest Ophthalmol Vis Sci. 2020 Mar 9;61(3):25. doi: 10.1167/iovs.61.3.25.

Abstract

PURPOSE

To investigate the underlying mechanisms for how the mouse Cx50-R205G point mutation, a homologue of the human Cx50-R198W mutation that is linked to cataract-microcornea syndrome, affects proper lens growth and fiber cell differentiation to lead to severe lens phenotypes.

METHODS

EdU labeling, immunostaining, confocal imaging analysis, and primary lens epithelial cell culture were performed to characterize the lens epithelial cell (LEC) proliferation and fiber cell differentiation in wild-type and Cx50-R205G mutant lenses in vivo and in vitro.

RESULTS

The Cx50-R205G mutation severely disrupts the lens size and transparency. Heterozygous and homozygous Cx50-R205G mutant and Cx50 knockout lenses all show decreased central epithelium proliferation while only the homozygous Cx50-R205G mutant lenses display obviously decreased proliferating LECs in the germinative zone of neonatal lenses. Cultured Cx50-R205G lens epithelial cells reveal predominantly reduced Cx50 gap junction staining but no change of the endoplasmic reticulum stress marker BiP. The heterozygous Cx50-R205G lens fibers show moderately disrupted Cx50 and Cx46 gap junctions while the homozygous Cx50-R205G lens fibers have drastically reduced Cx50 and Cx46 gap junctions with severely altered fiber cell shape in vivo.

CONCLUSIONS

The Cx50-R205G mutation inhibits both central and equatorial lens epithelial cell proliferation to cause small lenses. This mutation also disrupts the assembly and functions of both Cx50 and Cx46 gap junctions in lens fibers to alter fiber cell differentiation and shape to lead to severe lens phenotypes.

摘要

目的

研究导致小鼠 Cx50-R205G 点突变(与白内障-小角膜综合征相关的人类 Cx50-R198W 突变的同源突变)影响正常晶状体生长和纤维细胞分化,从而导致严重晶状体表型的潜在机制。

方法

通过 EdU 标记、免疫染色、共聚焦成像分析和原代晶状体上皮细胞培养,对野生型和 Cx50-R205G 突变体晶状体中晶状体上皮细胞(LEC)的增殖和纤维细胞分化进行了体内和体外研究。

结果

Cx50-R205G 突变严重破坏了晶状体的大小和透明度。杂合子和纯合子 Cx50-R205G 突变体和 Cx50 敲除晶状体均显示中央上皮细胞增殖减少,而仅纯合子 Cx50-R205G 突变体晶状体在新生晶状体的生发区显示明显减少的增殖性 LEC。培养的 Cx50-R205G 晶状体上皮细胞显示 Cx50 间隙连接染色明显减少,但内质网应激标志物 BiP 无变化。杂合子 Cx50-R205G 晶状体纤维显示 Cx50 和 Cx46 间隙连接中度破坏,而纯合子 Cx50-R205G 晶状体纤维则显示 Cx50 和 Cx46 间隙连接急剧减少,纤维细胞形状在体内发生严重改变。

结论

Cx50-R205G 突变抑制中央和赤道晶状体上皮细胞的增殖,导致晶状体变小。该突变还破坏了晶状体纤维中 Cx50 和 Cx46 间隙连接的组装和功能,从而改变纤维细胞的分化和形状,导致严重的晶状体表型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3442/7401428/4873db1f84a0/iovs-61-3-25-f001.jpg

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