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Effects of Elevated Pax6 Expression and Genetic Background on Mouse Eye Development

¹From the Division of Reproductive and Developmental Sciences, Genes and Development Group, University of Edinburgh, Edinburgh, Scotland, United Kingdom; the ³School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, United Kingdom; the ⁴Department of Clinical and Surgical Sciences, Ophthalmology Section, University of Edinburgh, Princess Alexandra Eye Pavilion, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom; and the ⁶Medical and Developmental Genetics Section, MRC Human Genetics Unit, Edinburgh, Scotland, United Kingdom. ²Present affiliations: Division of Cancer Studies, University of Birmingham, Cancer Research UK Institute for Cancer Studies, Birmingham, United Kingdom; ⁵Division of Reproductive and Developmental Sciences, Centre for Reproductive Biology, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh Scotland, United Kingdom.

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-typewild-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.