Retinal regeneration requires dynamic Notch signaling

Retinal damage in the adult zebrafish induces Muller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons. Notch signaling, which is a fundamental mechanism known to drive cell-cell communication, is required to maintain Muller glia in a quiescent state in the undamaged retina, and repression of Notch signaling is necessary for Muller glia to reenter the cell cycle. The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Muller glia-derived progenitor cells in a robust regeneration response. In contrast, mammalian Muller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss. Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Muller glia reprogramming for regeneration of the diseased human retina. Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Muller glia quiescence. In addition, multiomics datasets and functional studies indicate that additional Notch receptors, ligands, and target genes regulate cell proliferation and neurogenesis during the regeneration time course. Still, our understanding of Notch signaling during retinal regeneration is limited. To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration, investigation of additional aspects of the pathway, such as post-translational modification of the receptors, ligand endocytosis, and interactions with other fundamental pathways is needed. Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.

Automated summary

This article focuses on the importance of Notch signaling pathway in Müller glia reprogramming and retinal regeneration in zebrafish, and identifies the need for further research in various aspects of the pathway.