miRNAs and Müller Glia Reprogramming During Retina Regeneration

Abstract

The use of model systems that are capable of robust, spontaneous retina regeneration has allowed for the identification of genetic pathways and components that are required for retina regeneration. Complemented by mouse models in which retina regeneration can be induced after forced expression of key factors, altered chromatin accessibility, or inhibition of kinase/signaling cascades, a clearer picture of the key regulatory events that control retina regeneration is emerging. In all cases, Müller glia (MG) serve as an adult retinal stem cell that must be reprogrammed to allow for regeneration, with the end goal being to understand why regenerative pathways are blocked in mammals, but spontaneous in other vertebrates such as zebrafish. miRNAs have emerged as key gene regulatory molecules that control both development and regeneration in vertebrates. Here, we focus on a small subset of miRNAs that control MG reprogramming during retina regeneration and have the potential to serve as therapeutic targets for treatment of visual disorders and damage.

Keywords: Müller glia; miRNA; regeneration; retina; zebrafish.

Figure 1

Retina Regeneration in Zebrafish. In response to retinal damage or cell loss, zebrafish Müller Glia (MG) are activated and undergo dedifferentiation. Asymmetric division allows for self renewal and the generation of proliferating retinal progenitor cells (RPCs) which cluster along MG processes. As regeneration proceeds, the RPCs migrate to the site of damage before differentiating into any lost or damaged cell types.

Figure 2

Pathways and factors involved in retina regeneration. Following damage in the zebrafish retina, multiple pathways are activated controlling dedifferentiation of MG, re-entry into the cell cycle, asymmetric cell division, generation of proliferating RPCs, and eventual differentiation into replacement cell types. Green arrows represent factors that are active at the given step, whereas red arrows represent factors that are repressed or inactive at that time.

Figure 3

miRNAs and Retina Regeneration. The adult zebrafish retina expresses ~200 miRNAs but only a small subset of these miRNAs are differentially expressed during regeneration. RNAseq and other analyses after damage or during distinct stages of regeneration have identified miRNAs and select target mRNAs, as indicated. Green arrows represent miRNAs that are expressed or active at that given step, and red arrows represent miRNAs that are not expressed or inactive.