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Z. Yan, R. T. Libby, A. E. Kiernan; The Notch Ligand Jagged1 Has Multiple Roles in Ocular Development. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6330.
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In humans, heterozygous mutations in the Notch ligand Jagged1 (JAG1), causes Alagille syndrome, a disorder that includes anterior segment (AS) dysgenesis. Here, using JAG1 mouse mutants we examine the role of JAG1 in various ocular tissues.
A Jag1 knockout and conditional knockout were used in these studies. The Jag1 conditional allele was removed from the early developing optic cup (Six3-cre) or the developing retina and lens (Foxg1-cre). AS were analyzed in 2µ plastic sections that contained optic nerve. The expression of genes involved in optic cup patterning were examined by in situ hybridization. Molecular markers were used to determine if lens development was altered. At least three mice were assessed for each age and genotype.
Histological analysis of Jag1+/- eyes showed AS abnormalities including: abnormal pars plana, pars plicata transitions in the ciliary body; areas of hypoplastic or absent drainage structures; and areas of iris-cornea adhesion (synechia). Similarly, lenses from Jag1+/- adult mice had significant histopathology, including cataracts and iris adhesions. To begin to understand how and where JAG1 is involved in AS development, JAG1 was inactivated in the developing optic cup and lens. These eyes showed severe retinal and lens dysplasia. The retina demonstrated a thickened appearance and the lens was hypoplastic. Molecular analysis of lens development demonstrated that the mutant had a thin anterior epithelium and showed ectopic expression of p57kip2, suggesting premature differentiation of the anterior epithelium. We next investigated the role of JAG1 in AS structures derived from the optic cup. Mice lacking Jag1 in the developing optic cup had abnormal iridocorneal angle development, though this was not as severe as in the Jag1+/- mice. Msx1 and Otx1 expression in the developing optic cup was normal in these mice, suggesting that the AS defects did not arise from defects in ciliary margin specification.
Jag1 has several roles in ocular development. Jag1 expression in both the developing lens and optic cup is required for proper development of the irideocorneal angle.
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