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.

The microRNA miR-18a Links Proliferation and Inflammation During Photoreceptor Regeneration in the Injured Zebrafish Retina

“…In conclusion, this study is the rst to show that a miRNA regulates in ammation in the injured retina and is the rst to show that miR-18a is an important in ammatory regulator. This work adds to the growing body of knowledge that miRNAs are key regulators of neurogenesis throughout the central nervous system [67] and neuronal regeneration in the retina [15]. Importantly, the differential responses of Müller glia to in ammation following retinal injury in zebra sh compared with mammals could be key to unlocking the potential for mammalian Müller glia to robustly regenerate neurons.…”

“…Recent research has improved our understanding of the molecular pathways that regulate neuronal regeneration in the zebra sh retina [reviewed in 4,3,9,10]. The primary focus of this research has been on identifying the transcriptional mechanisms involved in neuronal regeneration, but recent studies show that post-transcriptional regulation by non-coding RNAs, and speci cally microRNAs (miRNAs), also play critical roles in retinal neuronal regeneration [11][12][13][14][15]. Of the more than 2600 mature miRNAs coded by the vertebrate genome [16], the functional roles of a very small number have been established in retinal regeneration.…”

Disruption of miR-18a alters proliferation, photoreceptor replacement kinetics, inflammatory signaling and microglia/macrophage numbers during retinal regeneration in zebrafish

“…In conclusion, this study is the first to show that the presence of a single miRNA is critical for inflammatory resolution in the injured/regenerating retina and is the first to show that miR-18a plays important roles in both inflammation and photoreceptor regeneration. This work adds to the growing body of knowledge that miRNAs are key regulators of neurogenesis throughout the central nervous system [79] and neuronal regeneration in the retina [15]. Importantly, the differential responses of Müller glia to inflammation following retinal injury in zebrafish compared with mammals could be key to unlocking the potential for mammalian Müller glia to robustly regenerate neurons.…”

“…Recent research has improved our understanding of the molecular pathways that regulate neuronal regeneration in the zebrafish retina [reviewed in 4,3,9,10]. The primary focus of this research has been on identifying the transcriptional mechanisms involved in neuronal regeneration, but recent studies show that post-transcriptional regulation by non-coding RNAs, and specifically microRNAs (miRNAs), also play critical roles in retinal neuronal regeneration [11][12][13][14][15]. Of the more than 2600 mature miRNAs coded by the vertebrate genome [16], the functional roles of a very small number have been established in retinal regeneration.…”

Retina stem cells, hopes and obstacles

“…Transcription factors and miRNAs have been shown to control the formation of new retinal neurons derived from endogenous SC. Particularly, miRNAs are involved in controlling the ability of MGCs in non-mammalian and mammalian vertebrates to generate new RPCs[ 91 ]. In zebrafish, which, as mentioned before, effectively regenerates the retina after injury[ 92 ], miR-216a regulates reprogramming in MGCs, maintaining them in a quiescent state in undamaged retina.…”