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Max B. Kelz, Jer R. Kuszak, Yinqing Yang, Wanchao Ma, Cathy Steffen, Kirsten Al-Ghoul, Ya-Jun Zhang, Jingshan Chen, Eric J. Nestler, Abraham Spector; ΔFosB-Induced Cataract. Invest. Ophthalmol. Vis. Sci. 2000;41(11):3523-3538.
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purpose. The objective of this study was to investigate a possible relationship
between posterior subcapsular cataract (PSC) formation and expression
of the transcription factor ΔFosB.
methods. Western blot analysis was performed on bitransgenic NSE-tTA,
TetOp-ΔFosB, and single-transgenic NSE-tTA control mice to determine
the pattern of ΔFosB expression within the eye. Light and scanning
electron microscopy and biochemical analyses were also performed.
results. In mice expressing ΔFosB, cataract developed that initially appeared
to be posterior subcapsular and gradually matured to involve the entire
lens. The enlarged posterior ends of developing secondary fibers curved
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 attenuated posterior capsule overlying the plaque ruptured and the
lens nucleus subluxated into the vitreous. Retinal damage was also
observed but only from postnatal day 65, a time when extensive lens
degeneration had already occurred. ΔFosB expression was observed well
before the detection of morphologic change in both the lens and the
retina. Within the lens, ΔFosB expression was found in both the
epithelium and fibers. The development of cataracts was a direct
consequence of ΔFosB expression and was not due to the disruption of
an endogenous gene by transgene integration since cataracts could be
prevented by silencing expression of ΔFosB by feeding bitransgenic
animals doxycycline (Dox). Moreover, cataracts were observed in
bitransgenic mice derived from two independent TetOp-ΔFosB founder
lines but not in single NSE-tTA transgenic controls. Cataractogenesis
was not a consequence of abnormal development, because mice conceived
and raised on Dox to prevent expression of ΔFosB also were subject to
formation of PSC when expression of ΔFosB was turned on in adult
animals by removing Dox. Examination of biochemical parameters
indicated that the earliest change observed was the disruption of
calcium homeostasis with a significant increase in Ca2+ influx, followed by a gradual but marked decrease in protein content.
Significant changes in certain metabolic parameters and protein
composition were also observed.
conclusions. The ΔFosB-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 ΔFosB-regulated target genes, it
should be possible to achieve a better understanding of the molecular
mechanisms through which PSC is formed.
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