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

• Published in: Investigative ophthalmology & visual science Vol. 50; no. 9; pp. 4045 - 4059
• Main Authors: Chanas, Simon A, Collinson, J. Martin, Ramaesh, Thaya, Dora, Natalie, Kleinjan, Dirk A, Hill, Robert E, West, John D
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.09.2009; Association for Research in Vision and Ophtalmology
• Subjects: Animals; Biological and medical sciences; Chimera - genetics; Crosses, Genetic; Eye - embryology; Eye Abnormalities - genetics; Eye and associated structures. Visual pathways and centers. Vision; Eye Proteins - genetics; Eye Proteins - metabolism; Female; Fluorescent Antibody Technique, Indirect; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - physiology; Genetic Predisposition to Disease; Genotype; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; In Situ Hybridization; Male; Medical sciences; Mice; Mice, Inbred A; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Ophthalmology; Paired Box Transcription Factors - genetics; Paired Box Transcription Factors - metabolism; PAX6 Transcription Factor; Polymerase Chain Reaction; Repressor Proteins - genetics; Repressor Proteins - metabolism; Vertebrates: nervous system and sense organs; Eye; Vertebrata; Mammalia; Mouse; Animal; Rodentia; Development; Genetics; Ophthalmology
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.07-1630

To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. 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. 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. 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.