Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Development. 2024 Jul 15;151(14). doi: 10.1242/dev.203062. Epub 2024 Jul 26.
In the injured zebrafish retina, Müller glial cells (MG) reprogram to adopt retinal stem cell properties and regenerate damaged neurons. The strongest zebrafish reprogramming factors might be good candidates for stimulating a similar regenerative response by mammalian MG. Myc proteins are potent reprogramming factors that can stimulate cellular plasticity in differentiated cells; however, their role in MG reprogramming and retina regeneration remains poorly explored. Here, we report that retinal injury stimulates mycb and mych expression and that, although both Mycb and Mych stimulate MG reprogramming and proliferation, only Mych enhances retinal neuron apoptosis. RNA-sequencing analysis of wild-type, mychmut and mycbmut fish revealed that Mycb and Mych regulate ∼40% and ∼16%, respectively, of the genes contributing to the regeneration-associated transcriptome of MG. Of these genes, those that are induced are biased towards regulation of ribosome biogenesis, protein synthesis, DNA synthesis, and cell division, which are the top cellular processes affected by retinal injury, suggesting that Mycb and Mych are potent MG reprogramming factors. Consistent with this, forced expression of either of these proteins is sufficient to stimulate MG proliferation in the uninjured retina.
在受伤的斑马鱼视网膜中,Müller 胶质细胞(MG)重新编程以获得视网膜干细胞特性并再生受损神经元。最强的斑马鱼重编程因子可能是刺激哺乳动物 MG 产生类似再生反应的良好候选物。Myc 蛋白是强有力的重编程因子,可以刺激分化细胞中的细胞可塑性;然而,它们在 MG 重编程和视网膜再生中的作用仍未得到充分探索。在这里,我们报告说视网膜损伤会刺激 mycb 和 mych 的表达,尽管 Mycb 和 Mych 都能刺激 MG 重编程和增殖,但只有 Mych 能增强视网膜神经元凋亡。对野生型、mychmut 和 mycbmut 鱼进行 RNA 测序分析表明,Mycb 和 Mych 分别调节约 40%和 16%的基因,这些基因有助于 MG 再生相关转录组。在这些基因中,诱导的基因偏向于核糖体生物发生、蛋白质合成、DNA 合成和细胞分裂的调控,这是受视网膜损伤影响最大的细胞过程,这表明 Mycb 和 Mych 是强有力的 MG 重编程因子。与此一致的是,这些蛋白质中的任何一种的强制表达都足以刺激未受伤视网膜中的 MG 增殖。