Unit of Gene Therapy and Stem Cell Biology, Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):E593-601. doi: 10.1073/pnas.1108297110. Epub 2013 Jan 28.
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.
表观遗传调节因子 Bmi1 控制着许多器官的增殖。细胞周期蛋白依赖性激酶（CDKs）等细胞周期蛋白的重新表达是神经退行性疾病中神经元凋亡的一个标志。在这里，我们研究了 Bmi1 作为细胞周期蛋白在神经元凋亡过程中的关键调节因子的潜在作用。我们发现，几种细胞周期蛋白在不同的视网膜变性模型中表达，并且在 Rd1 光感受器死亡过程中是必需的。删除 CDK 的下游靶标 E2f1 为 Rd1 小鼠提供了暂时的保护。最重要的是，Bmi1 的基因缺失为 Rd1 小鼠提供了广泛的光感受器存活和视网膜功能的改善，这是通过减少细胞周期标志物和调节因子来介导的，与 p16(Ink4a)和 p19(Arf)无关。这些数据表明 Bmi1 控制着与细胞周期相关的死亡过程，突出了该途径作为治疗视网膜营养不良的神经保护的一个有前途的治疗靶点。
