Pax2 Expression and Retinal Morphogenesis in the Normal andKrdMouse

Abstract

TheKidney and retinal defects (Krd)mouse carries a 7-cM transgene-induced deletion on chromosome 19 that includes thePax2locus. Adult mice heterozygous for theKrddeletion (Krd/+) are haploid forPax2and have a variable, semidominant phenotype characterized by structural defects of the kidney, retina, and optic disc. Renal and ocular anomalies present in heterozygousPax2mutants in both mice and humans support the hypothesis that haploinsufficiency ofPax2underlies theKrdphenotype. To understand the embryonic basis of ocular defects observed in adultKrd/+ mice, we used immunohistochemistry, digital three-dimensional reconstructions, and quantitative morphometry to examine Pax2 protein distribution and ocular development in normal andKrd/+ mice from E10.5 to P2. In +/+ embryos, Pax2 immunopositive (Pax2+) cells demarcate the embryonic fissure as it forms in the ventral optic cup and optic stalk. After closure of the embryonic fissure, Pax2 immunostaining disappears from the ventral retina, but persists in a cuff of cells encircling the developing optic disc, the site where ganglion cell axons exit the retina. InKrd/+ embryos, Pax2+ cells in the posterior optic cup and the optic stalk undergo abnormal morphogenetic movements and the embryonic fissure fails to form normally. This results in an abnormal organization of the Pax2+ cells and ganglion cell axons at the nascent optic disc. The abnormal morphogenetic movements of the Pax2+ cells in the embryonic retina and optic stalk and the initial misrouting of the ganglion cell axons give rise to retinal and optic disc defects observed in the adultKrd/+ mice.