Rb deficiency induces p21cip1 expression and delays retinal degeneration in rd1 mice.

Retinitis pigmentosa (RP) is a major cause of inherited blindness, and there is presently no cure for RP. Rd1 mouse is the most commonly used RP animal model. Re-expression of cell cycle proteins in post-mitotic neurons is considered an important mechanism of neurodegenerative diseases, including RP. The retinoblastoma tumor suppressor (Rb) is a major regulator of cell cycle progression, yet its role in rd1 mouse retina and related signaling pathways have never been analyzed. By crossing α-Cre, Rb ^f/f mice with rd1 mice, p21cip1 ^-/- mice, Cdk1 ^f/f mice and Cdk2 ^f/f mice, we established multiple rd1 mouse models with deletions of Rb gene, Cdkn1a (p21cip1) gene, Cdk1 and Cdk2 gene in the retina. Cdk inhibitor CR8 was injected into the vitreous of rd1 mouse to investigate its effects on photoreceptor survival. Rb gene knockout (KO) induces cell death in excitatory retinal neurons (rods, rod bipolar and ganglions) and ectopic proliferation of retinal cells; but it paradoxically delays the rod death of rd1 mice, which is primarily mediated by the Cdk inhibitor Cdkn1a (p21cip1). Interestingly, p21cip1 protects the ectopic dividing rd1 rod cells by inhibiting Cdk1 and Cdk2. However, inhibiting Cdk1 and Cdk2 in rd1 mice with non-dividing rods only has limited and transient protective effects. Our data suggest that there is no ectopic division of rd1 rod cells, and RbKO induces ectopic division but delays the death of rd1 rod cells. This reveals the important protective role of Rb-p21cip1-Cdk axis in rd1 rod cells. P21cip1 is a potential target for future therapy of RP.
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