Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Development. 2020 May 22;147(10):dev183418. doi: 10.1242/dev.183418.
Retinal regeneration is robust in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms that suppress the reprogramming of Müller glia into neurogenic progenitors is key to harnessing the regenerative potential of the retina Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this interaction are unknown. We used a chick model to investigate nuclear factor kappa B (NF-κB) signaling, a critical regulator of inflammation, during the reprogramming of Müller glia into proliferating progenitors. We find that components of the NF-κB pathway are dynamically regulated by Müller glia after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses, the formation of proliferating MGPCs. Following microglia ablation, the effects of NF-κB-agonists on MGPC-formation are reversed, suggesting that signals provided by reactive microglia influence how NF-κB impacts Müller glia reprogramming. We propose that NF-κB is an important signaling 'hub' that suppresses the reprogramming of Müller glia into proliferating MGPCs and this 'hub' coordinates signals provided by reactive microglia.
视网膜再生在一些冷血脊椎动物中很强大，但在温血脊椎动物中，这个过程无效。了解抑制 Müller 胶质细胞重编程为神经前体细胞的机制是利用视网膜再生潜能的关键。炎症和反应性小胶质细胞已知会影响 Müller 胶质细胞衍生的祖细胞（MGPC）的形成，但这种相互作用的机制尚不清楚。我们使用鸡模型来研究核因子 kappa B（NF-κB）信号，这是炎症的关键调节剂，在 Müller 胶质细胞重编程为增殖前体细胞的过程中。我们发现，NF-κB 途径的组成部分在神经元损伤或生长因子处理后会被 Müller 胶质细胞动态调节。NF-κB 的抑制增强了增殖性 MGPC 的形成，而激活则抑制了其形成。在小胶质细胞消融后，NF-κB 激动剂对 MGPC 形成的影响被逆转，这表明反应性小胶质细胞提供的信号影响 NF-κB 如何影响 Müller 胶质细胞重编程。我们提出 NF-κB 是一个重要的信号“枢纽”，它抑制 Müller 胶质细胞重编程为增殖性 MGPC，这个“枢纽”协调反应性小胶质细胞提供的信号。
