Mechanisms underlying Muller glia’s regenerative potential

摘要 致盲眼病，如青光眼、黄斑变性和视网膜色素变性可引起神经元。 退化并导致严重残疾。应用细胞移植修复丢失的神经元 有希望，但退化的视网膜可能会在经历了 伴随疾病进展的结构重塑。另一种方法是使用内源性干细胞治疗 视网膜神经元再生。值得注意的是，在斑马鱼中，穆勒胶质细胞可以作为干细胞并再生 视网膜神经元因损伤或疾病而丧失。虽然在斑马鱼和哺乳动物中都发现了Müler神经胶质细胞 视网膜，共享结构和功能；只有在鱼类中，它们才能再生新的神经元。在过去的十年里， 我们已经了解了很多关于调节Müler胶质细胞的遗传程序和信号通路 斑马鱼的重新编程和繁殖；然而，我们仍然缺乏对它们为什么可以 鱼类的再生反应，但哺乳动物没有。这条信息很可能存在于米勒·格里亚的 静止状态。有趣的是，Notch信号最近已经成为PRO和PRO之间的一个重要区别 斑马鱼视网膜中的再生Müler胶质细胞和哺乳动物视网膜中的非再生Müler神经胶质细胞。在……里面 斑马鱼Müler神经胶质细胞，Notch信号在基础状态下是活跃的，必须被抑制才能再生 然而，在小鼠中，出生后的Müler神经胶质细胞基本上不存在Notch信号。 有趣的是，Notch信号也与大脑中的放射状胶质干细胞有关，它的抑制是 对它们的细胞分裂和神经元再生是必要的。此外，Notch信令可以放大 随机事件的侧向抑制，从而可能驱动Müler细胞的异质性。斑马鱼Müler glia 异质性是指基因表达、自发增殖和对 视网膜损伤。在这项资助中，我们建议进一步表征未损伤的Müler神经胶质细胞的异质性 斑马鱼的视网膜，并将这种异质性与穆勒神经胶质细胞的再生潜力联系起来。此外，我们还将 研究Notch信号如何影响Müler胶质细胞转录组，以调节其再生特性。它 预计这些研究将为斑马鱼的视网膜再生提供新的见解，并导致新的 刺激哺乳动物Müler胶质细胞再生反应的策略。

Summary Blinding eye diseases, like glaucoma, macular degeneration, and retinitis pigmentosa cause neuronal degeneration and lead to severe disability. The restoration of lost neurons using cell transplantation holds promise, but the degenerating retina may prove resistant to exogenous cell integration as it undergoes structural remodeling with disease progression. An alternative approach is to use endogenous stem cells for retinal neuron regeneration. Remarkably, in zebrafish, Müller glia can function as stem cells and regenerate retinal neurons lost to injury or disease. Although Müller glia are found in both the zebrafish and mammalian retina, and share structure and function; only in fish do they regenerate new neurons. Over the past decade, we have learned a lot about the genetic programs and signaling pathways that regulate Müller glia reprogramming and proliferation in zebrafish; however, we still lack an understanding of why they can mount a regenerative response in fish, but not in mammals. It seems likely this information resides in Müller glia’s quiescent state. Interestingly, Notch signaling has recently emerged as an important difference between pro- regenerative Müller glia in the zebrafish retina and non-regenerative Müller glia in the mammalian retina. In zebrafish Müller glia, Notch signaling is active in the basal state and must be suppressed for regeneration to ensue; however, in mice Notch signaling is essentially absent from Müller glia beyond postnatal stages. Interestingly, Notch signaling is also associated with radial glial stem cells in the brain and its suppression is necessary for their cell division and neuronal regeneration. Furthermore, Notch signaling can amplify stochastic events by lateral inhibition and thereby, may drive Müller cell heterogeneity. Zebrafish Müller glia heterogeneity is suggested by differences in gene expression, spontaneous proliferation, and response to retinal injury. In this grant we propose to further characterize Müller glia cell heterogeneity in the uninjured zebrafish retina and connect this heterogeneity to Müller glia’s regenerative potential. In addition, we will investigate how Notch signaling impacts the Müller glia transcriptome to regulate its regenerative properties. It is anticipated that these studies will provide new insights into retina regeneration in zebrafish and lead to new strategies for stimulating Müller glia’s regenerative response in mammals.