Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development

The differentiation of neuronal cells in the developing mammalian retina is closely coupled to cell cycle arrest and proceeds in a highly organized ma nner. Cyclin D1, which regulates cell proliferation in many cells, also dri ves the proliferation of photoreceptor progenitors. In the mouse retina, cy clin D1 protein normally decreases as photoreceptors mature. To study the i mportance of the down-regulation of cyclin D1 during photoreceptor developm ent, we generated a transgenic mouse in which cyclin D1 was persistently ex pressed in developing photoreceptor cells. We observed numerous abnormaliti es in both photoreceptors and other nonphotoreceptor cells in the retina of these transgenic mice. In particular, we observed delayed opsin expression in developing photoreceptors and alterations in their number and morpholog y in the mature retina. These alterations were accompanied by disorganizati on of the inner nuclear and plexiform layers. The expression of cyclin D1 c aused excess photoreceptor cell proliferation and apoptosis. Loss of the p5 3 tumor suppressor gene decreased cyclin D1-induced apoptosis and led to mi croscopic hyperplasia in the retina. These findings are distinct from other mouse models in which the retinoblastoma gene pathway is disrupted and sug gest that the IRBP-cyclin D1 mouse model may recapitulate an early step in the development of retinoblastoma.