Truncated forms of Pax-6 disrupt lens morphology in transgenic mice

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 (A.D) 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 αA-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.