Persistent hyperplastic primary vitreous due to somatic mosaic deletion of the Arf tumor suppressor

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-type↔Arf^-/- 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 Pdgfrβ- 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.