Over-expression of a Dominant Negative Form of OREBP in the Lens Causes Congenital Cataract

Abstract

Purpose:To determine the role of a newly discovered osmotic response element binding protein (OREBP) in lens development and lens osmoregulation. OREBP is a transcription factor that regulates the expression of genes involved in osmoregulation. Methods:A dominant-negative form of OREBP that lacks the C-terminal transactivation domain was placed under the transcriptional control of the aA crystalline promoter. The transgene construct was used to create transgenic mouse lines. Lens morphology was determined by slit lamp examination, tissue sectioning and microscopy. Levels of mRNA of the lens were analyzed by real-time quantitative PCR. Results:Several lines of transgenic mice over-expressing the dominant negative form of OREBP lens-specifically at various levels have been generated. In transgenic lines with moderate transgene expression, morphological analysis showed that their lenses developed congenital pulverulent cataract. The higher expressing transgenic mouse lines showed liquefication of lens fibers. Analysis of aldose reductase mRNA indicates that lens osmoregulatory mechanism is down regulated in the transgenic mice. Conclusion:OREBP appeared to be important for lens development although the role is not clear at present.