The Arf Tumor Suppressor Gene Promotes Hyaloid Vascular Regression during Mouse Eye Development

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 6; pp. 3848 - 3853
• Main Authors: McKeller, Robyn N., Fowler, Jennifer L., Cunningham, Justine J., Warner, Nikita, Smeyne, Richard J., Zindy, Frederique, Skapek, Stephen X.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.03.2002; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Antibodies; Apoptosis; Arf gene; Biological Sciences; Blood vessels; Capsules; Cyclin-Dependent Kinase Inhibitor p16; Endothelial cells; Epithelial cells; Eye - blood supply; Eye - growth & development; Eye - metabolism; Eye - pathology; Eye Abnormalities - blood; Eye Abnormalities - metabolism; Eye Abnormalities - pathology; Eyes; Eyes & eyesight; Gene Deletion; Genes; Genes, p16 - physiology; Hyalin - metabolism; Mice; Mice, Inbred Strains; Mice, Knockout; Morphogenesis; Neovascularization, Physiologic; neurodevelopmental disorders; Neurons; p53 gene; Pathology; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; tumor suppressor genes; Tumor Suppressor Protein p14ARF - deficiency; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Protein p14ARF - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.052484199

A key tumor suppressor mechanism that is disrupted frequently in human cancer involves the ARF and p53 genes. In mouse fibroblasts, the Arf gene product responds to abnormal mitogenic signals to activate p53 and trigger either cell cycle arrest or apoptosis. Recent evidence indicates that Arf also has p53-independent functions that may contribute to its tumor suppressor activity. Using Arf-/-and p53-/-mice, we have discovered a p53-independent requirement for Arf in the developmental regression of the hyaloid vascular system (HVS) in the mouse eye. Arf is expressed in the vitreous of the eye and is induced before HVS regression in the first postnatal week. In the absence of Arf, failed HVS regression causes a pathological process that resembles persistent hyperplastic primary vitreous, a developmental human eye disease thought to have a genetic basis. These findings demonstrate an essential and unexpected role for Arf during mouse eye development, provide insights into the potential genetic basis for persistent hyperplastic primary vitreous, and indicate that Arf regulates vascular regression in a p53-independent manner. The latter finding raises the possibility that Arf may function as a tumor suppressor at least in part by regulating tumor angiogenesis.