Delta FosB-induced cataract

PURPOSE. The objective of this study was to investigate a possible relation ship between posterior subcapsular cataract (PSC) formation and expression of the transcription factor Delta FosB. METHODS. Western blot analysis was performed on bitransgenic NSE-tTA, TetOp -Delta FosB, and single-transgenic NSE-tTA control mice to determine the pa ttern of Delta FosB expression within the eye. Light and scanning electron microscopy and biochemical analyses were also performed. RESULTS. In mice expressing Delta FosB, cataract developed that initially a ppeared to be posterior subcapsular and gradually matured to involve the en tire lens. The enlarged posterior ends of developing secondary fibers curve d away from the visual axis to form an elevated opaque posterior plaque. As a result, posterior suture formation did not occur. At a later time, the a ttenuated posterior capsule overlying the plaque ruptured and the lens nucl eus subluxated into the vitreous. Retinal damage was also observed but only from postnatal day 65, a time when extensive lens degeneration had already occurred. Delta FosB expression was observed well before the detection of morphologic change in both the lens and the retina. Within the lens, Delta FosB expression was found in both the epithelium and fibers. The developmen t of cataracts was a direct consequence of Delta FosB expression and was no t due to the disruption of an endogenous gene by transgene integration sinc e cataracts could be prevented by silencing expression of Delta FosB by fee ding bitransgenic animals doxycycline (Dox). Moreover, cataracts were obser ved in bitransgenic mice derived from two independent TetOp-Delta FosB foun der lines but not in single NSE-tTA transgenic controls. Cataractogenesis w as not a consequence of abnormal development, because mice conceived and ra ised on Dox to prevent expression of Delta FosB also were subject to format ion of PSC when expression of Delta FosB was turned on in adult animals by removing Dox. Examination of biochemical parameters indicated that the earl iest change observed was the disruption of calcium homeostasis with a signi ficant increase in Ca2+ influx, followed by a gradual but marked decrease i n protein content. Significant changes in certain metabolic parameters and protein composition were also observed. CONCLUSIONS. The Delta FosB-induced cataract in which the major morphologic early event was the disruption of normal posterior fiber formation, may be a good model for PSC. By identifying Delta FosB regulated target genes, it should be possible to achieve a better understanding of the molecular mech anisms through which PSC is formed.