Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, United States.
Elife. 2020 May 12;9:e55137. doi: 10.7554/eLife.55137.
Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.
斑马鱼视网膜中的神经元变性会刺激 Müller 胶质细胞（MG）增殖，并产生多能祖细胞来修复视网膜。控制这种增殖对于成功再生至关重要。先前的研究报告称，视网膜损伤会刺激损伤反应性 MG 中的 pSmad3 信号。与这些发现相反，我们报告 pSmad3 表达仅限于静止的 MG，并在损伤反应性 MG 中受到抑制。我们的数据表明 Tgfb3 是负责调节 pSmad3 表达的配体。值得注意的是，尽管 Tgfb1b 或 Tgfb3 的过表达都可以刺激损伤视网膜中的 pSmad3 表达，但只有 Tgfb3 抑制了损伤依赖性 MG 增殖；这表明涉及非经典 Tgfb 信号通路。此外，抑制 Alk5、PP2A 或 Notch 信号可以挽救 Tgfb3 过表达斑马鱼中的 MG 增殖。最后，我们报告称，这种 Tgfb3 信号通路在斑马鱼 MG 中活跃，但在小鼠 MG 中不活跃，这可能导致鱼和哺乳动物的 MG 具有不同的再生能力。
