Role of INK4a locus in normal eye development and cataract genesis

The murine INK4a locus encodes the critical tumor suppressor proteins, p16INK4a and p19ARF. Mice lacking both p16INK4a and p19ARF (INK4a−/−) in their FVB/NJ genetic backgrounds developed cataracts and microophthalmia. Histopathologically, INK4a−/− mice showed defects in the developmental regression of the hyaloid vascular system (HVS), retinal dysplasia, and cataracts with numerous vacuolations, closely resembling human persistent hyperplastic primary vitreous (PHPV). Ocular defects, such as retinal fold and abnormal migration of lens fiber cells, were observed as early as embryonic day (E) 15.5, thereby resulting in the abnormal differentiation of the lens. We also found that ectopic expression of p16INK4a resulted in the induction of γF-crystallin, suggesting an important role of INK4a locus during mouse eye development, and also providing insights into the potential genetic basis of human cataract genesis.