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1 From the The Department of Biological Sciences, The University of Delaware, Newark; 2 The Departments of Ophthalmology and Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York; and the 3 Laboratory of Molecular and Developmental Biology, National Eye Institute, Bethesda, Maryland.
PURPOSE. Extensive literature shows that Pax-6 is critical for lens development and that Pax-6 mutations can result in aniridia in humans. In addition, it has been reported that truncated Pax-6 molecules can act as dominant–negative repressors of wild-type Pax-6 activity in cultured cells. This study was designed to determine whether Pax-6 molecules without either the activation domain (AD) or the homeodomain (HD) and the AD can function as dominant–negative repressors in vivo and alter the phenotype of the lens.
METHODS. Transgenic mice were created harboring the 
A-crystallin promoter
linked to a cDNA encoding either a truncated Pax-6 without the C
terminus (paired domain [PD] + homeodomain) or Pax-6 consisting of
only the PD. The phenotype of the resultant animals was investigated by
light and electron microscopy as well as atomic absorption
spectroscopy.
RESULTS. Two lines of PD + HD mice and three lines of PD mice were generated, all of which exhibit posterior nuclear and/or cortical cataracts of variable severity. The lenses from mice transgenic for either Pax-6 truncation are smaller and more hydrated than normal. Morphologically, the mice expressing the PD + HD of Pax-6 have swollen lens fibers with attenuated ball-and-socket junctions. In contrast, the lenses from mice overexpressing the PD of Pax-6 have posterior nuclear cataracts composed of cell debris, whereas the remaining fiber cells appear generally normal.
CONCLUSIONS. The presence of truncated Pax-6 protein in the lens is sufficient to induce cataract in a wild-type genetic background. The simplest explanation for this phenomenon is a dominant–negative effect; however, a number of other possible mechanisms are presented.
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