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Persistent Hyperplastic Primary Vitreous Due to Somatic Mosaic Deletion of the Arf Tumor Suppressor

¹From the Departments of Oncology and ³Biostatistics, St. Jude Children’s Research Hospital and the ⁴Departments of Ophthalmology and Anatomy and ²Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee.

PURPOSE. Mice lacking the Arf tumor-suppressor gene develop eye disease reminiscent of persistent hyperplastic primary vitreous (PHPV). The current work explores mechanisms by which Arf promotes eye development, and its absence causes a PHPV-like disease.

METHODS. Chimeric mice were made by fusing wild-type and Arf^–/– morulae. In these experiments, wild-type cells are identified by transgenic expression of GFP from a constitutive promoter. PCR-based genotyping and quantitative analyses after immunofluorescence staining of tissue and cultured cells documented the relative contribution of wild-type and Arf^–/– cells to different tissues in the eye and different types of cells in the vitreous.

RESULTS. The contributions of the Arf^–/– lineage to the tail DNA, cornea, retina, and retina pigment epithelium (RPE) correlated with each other in wild-typeArf^–/– chimeric mice. Newborn chimeras had primary vitreous hyperplasia, evident as a retrolental mass. The mass was usually present when the proportion of Arf^–/– cells was relatively high and absent when the Arf^–/– proportion was low. The Pdgfrß- and Sma-expressing cells within the mass arose predominantly from the Arf^–/– population. Ectopic Arf expression induced smooth muscle proteins in cultured pericyte-like cells, and Arf and Sma expression overlapped in hyaloid vessels.

CONCLUSIONS. In the mouse model, loss of Arf in only a subset of cells causes a PHPV-like disease. The data indicate that both cell autonomous and non–cell autonomous effects of Arf may contribute to its role in vitreous development.

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