α3Cx46基因敲除小鼠的年龄相关性白内障取决于一种钙蛋白酶3同工型。
Age-related cataracts in alpha3Cx46-knockout mice are dependent on a calpain 3 isoform.
作者信息
Tang Yajun, Liu Xiangyang, Zoltoski Rebecca K, Novak Layne A, Herrera R Antonio, Richard Isabelle, Kuszak Jer R, Kumar Nalin M
机构信息
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
出版信息
Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2685-94. doi: 10.1167/iovs.06-0926.
PURPOSE
Previous studies have demonstrated that in 129alpha3Cx46-/- mice, age-related nuclear cataract is formed. In the present study, a more in vivo-relevant model was generated to test the hypothesis that the calpain 3 gene is involved in age-related nuclear cataractogenesis in alpha3Cx46 knockout mice.
METHODS
To test the hypothesis that the calpain 3 gene is involved in age-related nuclear cataractogenesis in alpha3Cx46 knockout mice, 129alpha3Cx46-/- and CAPN3-/- mice were mated to generate homozygous double-knockout (dKO) mice. Lenses from the mice were examined by visual observation, laser scan analysis, and histologic and biochemical methods.
RESULTS
In the absence of the CAPN3 gene, the formation of a cataract was delayed, and its appearance was changed to a more diffuse, pulverulent type. Unlike in the 129alpha3Cx46-/- mouse, cleavage of gamma-crystallin was not detected in the dKO mouse. In both 129alpha3Cx46-/- and dKO mice, total Ca2+ increased.
CONCLUSIONS
The present study shows for the first time that calpain 3 is necessary for the formation of age-dependent nuclear cataracts in alpha3Cx46-/- mice. Evidence that the calpain 3 gene is directly involved in, or part of the pathway that leads to, gamma-crystallin cleavage is presented. These results are consistent with the hypothesis that the loss of alpha3Cx46 leads to increased levels of Ca2+ ions, and this increase activates the CAPN3 isoform, Lp82/85, which results in the formation of a nuclear cataract.
目的
先前的研究表明，在129α3Cx46基因敲除小鼠中会形成年龄相关性核性白内障。在本研究中，构建了一个更符合体内情况的模型，以验证钙蛋白酶3基因参与α3Cx46基因敲除小鼠年龄相关性核性白内障发生的假说。
方法
为验证钙蛋白酶3基因参与α3Cx46基因敲除小鼠年龄相关性核性白内障发生的假说，将129α3Cx46基因敲除小鼠与CAPN3基因敲除小鼠交配，以产生纯合双基因敲除（dKO）小鼠。通过肉眼观察、激光扫描分析以及组织学和生化方法对小鼠晶状体进行检查。
结果
在缺乏CAPN3基因的情况下，白内障的形成延迟，其外观变为更弥散的粉末状。与129α3Cx46基因敲除小鼠不同，在dKO小鼠中未检测到γ-晶状体蛋白的裂解。在129α3Cx46基因敲除小鼠和dKO小鼠中，总钙含量均增加。
结论
本研究首次表明，钙蛋白酶3对于α3Cx46基因敲除小鼠年龄依赖性核性白内障的形成是必需的。提出了钙蛋白酶3基因直接参与或作为导致γ-晶状体蛋白裂解途径一部分的证据。这些结果与α3Cx46缺失导致钙离子水平升高，进而激活CAPN3亚型Lp82/85，最终导致核性白内障形成的假说一致。
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