INFLUENCE OF PAX6 GENE DOSAGE ON DEVELOPMENT - OVEREXPRESSION CAUSES SEVERE EYE ABNORMALITIES

Aniridia in man and Small eye in mice are semidominant developmental d isorders caused by mutations within the paired box gene PAX6. Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes a nd nasal cavities and exhibit brain abnormalities. To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus. When crosse d onto the Small eye background, the transgene rescues the mutant phen otype. Strikingly, mice carrying multiple copies on a wild-type backgr ound show specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Thus, at least five different eye p henotypes are associated with changes in PAX6 expression. We provide e vidence that not only reduced, but also increased levels of transcript ional regulators can cause developmental defects.