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

PURPOSE. Extensive Literature shows that Pax-6 is critical fur lens develop ment 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-n egative repressors of wild-type Pax-6 activity in cultured cells. This stud y was designed to determine whether Pax-6 molecules without either the acti vation domain (AD) or the homeodomain (HD) and the AD can function as domin ant-negative repressors in vivo and alter the phenotype of the lens. METHODS. Transgenic mice were created harboring the alpha A-crystallin prom oter linked to a cDNA encoding either a truncated Pax-6 without the C termi nus (paired domain [PD] + homeodomain) or Pax-6 consisting of only the PD. The phenotype of the resultant animals was investigated by light and electr on microscopy as well as atomic absorption spectroscopy. RESULTS. Two lines of PD + HD mice and three lines of PD mice were generate d,all of which exhibit posterior nuclear and/or cortical cataracts of varia ble severity. The lenses from mice transgenic for either Pax-6 truncation a re smaller and more hydrated than normal. Morphologically, the mice express ing 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 o f Pax-6 have posterior nuclear cataracts composed of cell debris, whereas t he remaining fiber cells appear generally normal. CONCLUSIONS. The presence of truncated Pax-6 protein in the lens is suffici ent to induce cataract in a wild-type genetic background. The simplest expl anation for this phenomenon is a dominant-negative effect; however, a numbe r of other possible mechanisms are presented.