Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression.
Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression.
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DOI：
10.1186/1471-2199-10-10
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发表时间：
2009-02-19
影响因子：
--
通讯作者：
Hu L
中科院分区：
文献类型：
--
作者：
Shi X;Cui B;Wang Z;Weng L;Xu Z;Ma J;Xu G;Kong X;Hu L
热休克转录因子4(HSF4)突变与常染色体显性遗传性板层白内障和Marner白内障相关。HSF4基因的破坏会导致小鼠晶状体缺陷，这表明在晶状体发育过程中，纤维细胞分化需要HSF4。然而，HSF4和晶体蛋白之间的关系以及HSF4维持晶状体透明度的详细机制都不是完全清楚的。为了确定HSF4缺失导致的潜在生物医学和生理机制如何促进白内障的形成，我们建立了一种HSF4基因敲除的小鼠模型。我们发现HSF4基因敲除小鼠(HSF4-/-)部分模仿了由HSF4突变引起的人类白内障。定量-聚合酶链式反应分析显示，几个与白内障相关的基因，包括γS晶体蛋白(Crygs)和晶状体特异的珠状丝蛋白1和2(Bfsp1和Bfsp2)，在HSF4-/-小鼠的晶状体中下调。利用双荧光素酶系统进行的转录活性分析表明，这些与白内障相关的基因是HSF4的直接下游靶标。HsF4对γS晶体蛋白的影响以HsF4-/-，rncat杂交所见的白内障发生为例。全晶体裂解产物的2D电泳分析显示，与野生型小鼠相比，8周大的hsf4-/-小鼠的表达模式不同，包括一些αA-晶状体蛋白修饰的丢失和γ-晶状体蛋白蛋白的表达减少。我们的结果表明，HSF4对晶状体的发育非常重要，HSF4基因的破坏至少通过三条途径导致白内障：1)γ-晶体蛋白，特别是γS-晶体蛋白的下调；2)晶状体珠丝表达的减少；以及3)αA-晶体蛋白翻译后修饰的丢失。
Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the Hsf4 gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. However, neither the relationship between HSF4 and crystallins nor the detailed mechanism of maintenance of lens transparency by HSF4 is fully understood. In an attempt to determine how the underlying biomedical and physiological mechanisms resulting from loss of HSF4 contribute to cataract formation, we generated an Hsf4 knockout mouse model. We showed that the Hsf4 knockout mouse (Hsf4-/-) partially mimics the human cataract caused by HSF4 mutations. Q-PCR analysis revealed down-regulation of several cataract-relevant genes, including γS-crystallin (Crygs) and lens-specific beaded filament proteins 1 and 2 (Bfsp1 and Bfsp2), in the lens of the Hsf4-/- mouse. Transcription activity analysis using the dual-luciferase system suggested that these cataract-relevant genes are the direct downstream targets of HSF4. The effect of HSF4 on γS-crystallin is exemplified by the cataractogenesis seen in the Hsf4-/-,rncat intercross. The 2D electrophoretic analysis of whole-lens lysates revealed a different expression pattern in 8-week-old Hsf4-/- mice compared with their wild-type counterparts, including the loss of some αA-crystallin modifications and reduced expression of γ-crystallin proteins. Our results indicate that HSF4 is sufficiently important to lens development and disruption of the Hsf4 gene leads to cataracts via at least three pathways: 1) down-regulation of γ-crystallin, particularly γS-crystallin; 2) decreased lens beaded filament expression; and 3) loss of post-translational modification of αA-crystallin.
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影响因子：
3.4
作者：
Ibaraki, N;Chen, SC;Reddy, VN
通讯作者：
Reddy, VN
影响因子：
7.8
作者：
Goulielmos, G;Gounari, F;Remington, S;Muller, S;Haner, M;Aebi, U;Georgatos, SD
通讯作者：
Georgatos, SD
影响因子：
3.5
作者：
Jungblut, PR;Otto, A;Klose, J
通讯作者：
Klose, J
影响因子：
19
作者：
Quinlan, RA;Carter, JM;Prescott, AR
通讯作者：
Prescott, AR
影响因子：
9.8
作者：
Conley, YP;Erturk, D;Gorin, MB
通讯作者：
Gorin, MB