Mechanisms underlying Muller glia’s regenerative potential

总结 致盲性眼病，如青光眼、黄斑变性和视网膜色素变性， 退化并导致严重残疾。使用细胞移植恢复丢失的神经元 希望，但退化的视网膜可能会在经历过程中对外源细胞整合产生抵抗力 结构重塑与疾病进展。另一种方法是使用内源性干细胞， 视网膜神经元再生值得注意的是，在斑马鱼中，Müller胶质细胞可以作为干细胞发挥作用并再生 视网膜神经元因损伤或疾病而丧失。虽然缪勒神经胶质细胞在斑马鱼和哺乳动物中都有发现， 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缪勒神经胶质细胞的遗传程序和信号通路的信息， 然而，我们仍然缺乏对为什么它们可以在斑马鱼中重新编程和增殖的理解。 鱼类的再生反应，而不是哺乳动物。看来这一信息可能存在于缪勒神经胶质细胞中 静止状态有趣的是，Notch信号最近已经成为亲- 斑马鱼视网膜中的再生Müller神经胶质和哺乳动物视网膜中的非再生Müller神经胶质。在 在斑马鱼Müller神经胶质中，Notch信号在基础状态下是活跃的，并且必须被抑制才能再生， 然而，在小鼠中，Notch信号在出生后阶段之后基本上不存在于Müller胶质细胞中。 有趣的是，Notch信号传导也与大脑中的放射状胶质干细胞相关，并且其抑制作用与神经胶质干细胞相关。 细胞分裂和神经元再生所必需的。此外，Notch信号可以放大 随机事件通过侧向抑制，从而可能驱动Müller细胞异质性。斑马鱼神经胶质 基因表达、自发增殖和对肿瘤细胞增殖的反应的差异表明了肿瘤细胞的异质性。 视网膜损伤在这项研究中，我们建议进一步描述未受伤的Müller胶质细胞的异质性。 斑马鱼视网膜，并将这种异质性与Müller神经胶质细胞的再生潜力联系起来。此外，我们将 研究Notch信号如何影响Müller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视网膜再生提供新的见解，并导致新的 刺激哺乳动物Müller神经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.