DeltaFosB-induced cataract.
OBJECTIVE
The objective of this study was to investigate a possible relationship between posterior subcapsular cataract (PSC) formation and expression of the transcription factor DeltaFosB.


METHODS
Western blot analysis was performed on bitransgenic NSE-tTA, TetOp-DeltaFosB, and single-transgenic NSE-tTA control mice to determine the pattern of DeltaFosB expression within the eye. Light and scanning electron microscopy and biochemical analyses were also performed.


RESULTS
In mice expressing DeltaFosB, 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. DeltaFosB expression was observed well before the detection of morphologic change in both the lens and the retina. Within the lens, DeltaFosB expression was found in both the epithelium and fibers. The development of cataracts was a direct consequence of DeltaFosB expression and was not due to the disruption of an endogenous gene by transgene integration since cataracts could be prevented by silencing expression of DeltaFosB by feeding bitransgenic animals doxycycline (Dox). Moreover, cataracts were observed in bitransgenic mice derived from two independent TetOp-DeltaFosB 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 DeltaFosB also were subject to formation of PSC when expression of DeltaFosB 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 Ca(2+) 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 DeltaFosB-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 DeltaFosB-regulated target genes, it should be possible to achieve a better understanding of the molecular mechanisms through which PSC is formed.
Kelz
M B
MB
Laboratory of Molecular Psychiatry and Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut, USA.
Kuszak
J R
JR
Yang
Y
Y
Ma
W
W
Steffen
C
C
Al-Ghoul
K
K
Zhang
Y J
YJ
Chen
J
J
Nestler
E J
EJ
Spector
A
A
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002386:Cataract / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003459:Crystallins / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D007906:Lens Subluxation / Q000209:etiology; D007908:Lens, Crystalline / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D009929:Organ Size; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012413:Rubidium / Q000378:metabolism
D003459:Crystallins; D016760:Proto-Oncogene Proteins c-fos; D012413:Rubidium; D004318:Doxycycline; D002118:Calcium