Del Debbio Carolina Beltrame, Mir Qulsum, Parameswaran Sowmya, Mathews Saumi, Xia Xiaohuan, Zheng Li, Neville Andrew J, Ahmad Iqbal
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2016 Mar 24;11(3):e0152025. doi: 10.1371/journal.pone.0152025. eCollection 2016.
Müller glia (MG), the sole glial cells generated by retinal progenitors, have emerged as a viable cellular target for therapeutic regeneration in degenerative blinding diseases, as they possess dormant stem cell properties. However, the mammalian MG does not display the neurogenic potential of their lower vertebrate counterparts, precluding their practical clinical use. The answer to this barrier may be found in two interlinked processes underlying the neurogenic potential, i.e., the activation of the dormant stem cell properties of MG and their differentiation along the neuronal lineage. Here, we have focused on the former and examined Notch signaling-mediated activation of MG. We demonstrate that one of the targets of Notch signaling is the cyclin-dependent kinase inhibitor (CKI), p27Kip1, which is highly expressed in quiescent MG. Notch signaling facilitates the activation of MG by inhibiting p27Kip1 expression. This is likely achieved through the Notch- p27Kip1 and Notch-Skp2-p27Kip1 axes, the former inhibiting the expression of p27Kip1 transcripts and the latter levels of p27Kip1 proteins by Skp2-mediated proteasomal degradation. Thus, Notch signaling may facilitate re-entry of MG into the cell cycle by inhibiting p27Kip1 expression both transcriptionally and post-translationally.
穆勒胶质细胞（MG）是视网膜祖细胞产生的唯一胶质细胞，由于其具有休眠干细胞特性，已成为退行性致盲疾病治疗性再生的一个可行细胞靶点。然而，哺乳动物的MG并不具备低等脊椎动物对应细胞的神经发生潜能，这限制了它们在实际临床中的应用。解决这一障碍的答案可能在于神经发生潜能背后的两个相互关联的过程，即MG休眠干细胞特性的激活及其沿神经元谱系的分化。在此，我们专注于前者，研究了Notch信号介导的MG激活。我们证明，Notch信号的靶点之一是细胞周期蛋白依赖性激酶抑制剂（CKI）p27Kip1，它在静止的MG中高度表达。Notch信号通过抑制p27Kip1表达促进MG的激活。这可能是通过Notch-p27Kip1和Notch-Skp2-p27Kip1轴实现的，前者抑制p27Kip1转录本的表达，后者通过Skp2介导的蛋白酶体降解降低p27Kip1蛋白水平。因此，Notch信号可能通过在转录和翻译后抑制p27Kip1表达，促进MG重新进入细胞周期。
