Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

Abstract

The epigenetic regulator Bmi1 controls proliferation in many organs. Reexpression of cell cycle proteins such as cyclin-dependent kinases (CDKs) is a hallmark of neuronal apoptosis in neurodegenerative diseases. Here we address the potential role of Bmi1 as a key regulator of cell cycle proteins during neuronal apoptosis. We show that several cell cycle proteins are expressed in different models of retinal degeneration and required in the Rd1 photoreceptor death process. Deleting E2f1, a downstream target of CDKs, provided temporary protection in Rd1 mice. Most importantly, genetic ablation of Bmi1 provided extensive photoreceptor survival and improvement of retinal function in Rd1 mice, mediated by a decrease in cell cycle markers and regulators independent of p16 Ink4a and p19 Arf . These data reveal that Bmi1 controls the cell cycle-related death process, highlighting this pathway as a promising therapeutic target for neuroprotection in retinal dystrophies.blindness | neurodegeneration | polycomb

Retinal development anomalies and cone photoreceptors degeneration upon Bmi1 deficiency

“…Also, whether acute Bmi1 inhibition in Rd1 mice can prevent rod degeneration remains to be demonstrated, as this would be more relevant to a clinical context. Interestingly, the outer segment of cones is abnormal in Rd1/Bmi1 −/− mice, as shown using S-opsin immunolabeling, suggesting rod-independent cone degeneration (Zencak et al, 2013). This is consistent with our overall findings suggesting cell-autonomous degeneration of cones in Bmi1 −/− mice.…”

“…In previous work, it was proposed that Bmi1 inactivation could prevent rod and cone photoreceptor degeneration in Rd1 mice, a model of retinitis pigmentosa (Zencak et al, 2013). Rd1 mice carry a mutation in Pde6b, which is only expressed in rods.…”

“…Thus, cone degeneration in Rd1 mice is thought to be secondary to the loss of trophic support provided by rods. As apoptosis of rod photoreceptors in Rd1 mice is preceded by cell cycle re-entry and activation of cyclin dependent kinases (CDKs), it was suggested that loss of Bmi1 provides neuroprotection by blocking CDK activation and thus cell cycle re-entry of rods (Marigo, 2007;Sancho-Pelluz et al, 2008;Zencak et al, 2013). Here, we found that Bmi1 deficiency was associated with the activation of several cell cycle inhibitors in the retina such as p16 INK4a , p19 ARF , Chk2 and p53, consistent with the general function of Bmi1 in inhibiting the p16…”

Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets

“…Interestingly these neurons also expressed CDK4 and CDK2 when cell death was studied in vitro facilitating the molecular dissection of their actions. In the retina of the Rd1 mouse, bearing a mutation in the Pde6b gene coding for a protein of the phototransduction pathway, the number of photoreceptors expressing CDK4 is 4-5 times more elevated than the number of photoreceptors containing CDK2 (Zencak et al 2013). Moreover, transgenic rats affected by a dominant mutation in the rhodopsin gene also express CDK4 during the time course of photoreceptor cell death process.…”

“…Moreover, transgenic rats affected by a dominant mutation in the rhodopsin gene also express CDK4 during the time course of photoreceptor cell death process. Acute injury similarly induces CDK4 expression in the retina and the brain consecutively to high light exposure and stroke respectively (Zencak et al 2013;Osuga et al 2000), suggesting that these kinases may have an important role in the process of cell death for both inherited diseases and acute injury. In all these different disease cases, the expression of the CDKs was observed in correct location, the nucleus, suggesting that other proteins of the cell cycle regulation may also be expressed during this degenerative stage.…”