Abstract
BackgroundHeat-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.ResultsIn 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.ConclusionOur 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.
Highlights
Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract
It has a unique role in the development of the lens at the late embryonic and postnatal stages of mouse development; disruption of the Hsf4 gene leads to cataracts via multiple pathways
The Hsf4-/- mouse exhibits aberrant fiber development in the pericentric region of the lens, partially mimicking human HSF4 mutation cataracts In order to examine the function of HSF4 in lens formation in detail, we generated targeted disruption of the mouse Hsf4 gene by homologous recombination of 129S3 embryonic stem (ES) cells
Summary
Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the Hsf gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. Cataract development is the leading cause of defective vision in humans, and cataracts can be classified as either congenital or age-related. The first group of genes, including Pax, Six, Rx, Sox, Pitx and MAF, consists of transcription factors at the top of the hierarchy of lens development that are required for the early stages of lens development [3]. Mutations in these genes prevent correct formation of the primary lens fibers, leading to most severe lens defect phenotypes. The relationship between transcription factors and lens structural genes warrants further study
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