Purpose: To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development.
Methods: Histologic features of eyes from hemizygous PAX77(+/-) transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77(+/-)<-->wild-type and control wild-type<-->wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77(+/-) mice.
Results: PAX77(+/-) mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6(+/-) heterozygotes (low Pax6 dose). Some previously reported PAX77(+/-) eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77(+/-)<-->wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77(+/-) cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77(+/-) and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77(+/-) and wild-type cells to mix normally and overrepresentation of PAX77(+/-) in the lens epithelium and RPE.
Conclusions: The extent of PAX77(+/-) eye abnormalities depended on PAX77(+/-) genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77(+/-) genotype. Abnormal cell mixing between PAX77(+/-) and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77(+/-)<-->wild-type and Pax6(+/-)<-->wild-type chimeras may reflect differences in the levels of PAX77(+/-) and Pax6(+/-) contributions to chimeric lenses.