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Lisheng Chen, Philip J Gage; Pitx2+/- mice have anterior segment defects and early-onset glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2432.
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© ARVO (1962-2015); The Authors (2016-present)
Heterozygous mutations in PITX2, encoding the paired-like homeodomain transcription factor 2, cause Axenfeld-Rieger Syndrome (ARS), including developmental defects in anterior eye structures and a 50-70% risk of glaucoma. However, Pitx2+/- mice have never been assessed for comparable phenotypes. We tested the hypothesis that Pitx2+/- mice exhibit characteristics of glaucoma, and are a useful model for studying the mechanisms underlying initiation and progression of the disease.
Intraocular pressure (IOP) of wild type and Pitx2+/- mice was measured using a TonoLab tonometer at regular intervals from 3 weeks through 6 months of age. SD-OCT imaging was used on the same animals to assess morphologic changes in the anterior segments and optic nerve head over the same time course. Retinal ganglion cell numbers in 3-week and 6-month old control and heterozygous eyes were quantified following whole mount staining for a ganglion cell marker RBPMS. Optic nerves from 6-month old animals were assessed on JB-4 plastic sections stained with para-phenyl diamine.
Pitx2+/- mice have significantly elevated IOP compared to control litter mates by the earliest time point examined (3 weeks). PITX2+/- eyes exhibit variable iridocorneal adhesions that cause angle closure as early as 5 weeks of age. Optic nerve heads of Pitx2+/- eyes display a severe cupping phenotype at 3 weeks, the earliest time point examined. Although retinal ganglion cells appear unaffected in 3-week old Pitx2+/- mice, ganglion cell numbers are dramatically decreased in 6-month old Pitx2+/- mice compared to Pitx2+/+ litter mates. In parallel, optic nerves of 6-month Pitx2+/- mice exhibit moderate to severe axonal degeneration.
Pitx2+/- mice have highly penetrant changes in the anterior segment, ganglion cells, and optic nerve that are consistent with closed angle glaucoma. Certain phenotypes, including elevated IOP and optic nerve head cupping, appear to be congenital. Collectively, these data suggest that Pitx2+/- mice provide an animal model for Axenfeld-Rieger Syndrome, and a unique opportunity to study mechanisms underlying glaucoma initiation and progression.
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