Activating the regenerative potential of Müller glia cells in a regeneration-deficient retina

Abstract

Regeneration responses in animals are widespread across phyla. To identify molecular players that confer regenerative capacities to non-regenerative species is of key relevance for basic research and translational approaches. Here, we report a differential response in retinal regeneration between medaka (Oryzias latipes) and zebrafish (Danio rerio). In contrast to zebrafish, medaka Müller glia (olMG) cells behave like progenitors and exhibit a restricted capacity to regenerate the retina. After injury, olMG cells proliferate but fail to self-renew and ultimately only restore photoreceptors. In our injury paradigm, we observed that in contrast to zebrafish, proliferating olMG cells do not maintain sox2 expression. Sustained sox2 expression in olMG cells confers regenerative responses similar to those of zebrafish MG (drMG) cells. We show that a single, cell-autonomous factor reprograms olMG cells and establishes a regeneration-like mode. Our results position medaka as an attractive model to delineate key regeneration factors with translational potential.

Igf signalling uncouples retina growth from body size by modulating progenitor cell division

“…To functionally validate the potential of cndp-expressing cells, we employed a Cre/loxP-29 mediated lineage tracing approach. We generated a construct where a Tamoxifen-inducible 30 Cre ERT2 was expressed under the control of the cndp promoter ( Fig. 5B) and combined it with 31 the GaudíRSG red-switch-green reporter line (Centanin et al, 2014).…”

Rebuilding the Retina: Prospects for Müller Glial-mediated Self-repair

“…In contrast to the zebrafish MG, Medaka MG do not divide asymmetrically after cell-cycle re-entry or produce neurogenic clusters. 59 The MG of amphibians are typically quiescent in the uninjured state. However, they too can be induced to proliferate in response to injury.…”

“…Indeed, recent studies into the transcriptional pathways regulating these responses have revealed striking differences. 59,69,70 Sox2, an important transcription factor in retinal development, continues to be expressed at low levels in MG and amacrine cells in the adult retina of both zebrafish and Medaka fish. 59,69 After light-induced damage, Sox2 expression is significantly increased in the zebrafish MG as they undergo proliferation.…”

“…59,69,70 Sox2, an important transcription factor in retinal development, continues to be expressed at low levels in MG and amacrine cells in the adult retina of both zebrafish and Medaka fish. 59,69 After light-induced damage, Sox2 expression is significantly increased in the zebrafish MG as they undergo proliferation. Gorsuch and colleagues 69 further demonstrated that Sox2 is necessary, and ectopic expression of Sox2 is sufficient, to induce zebrafish MG proliferation.…”

A Comparative Perspective on Brain Regeneration in Amphibians and Teleost Fish

“…For example, the red spotted newt ( Notophthalmus viridescens ) and the axolotl ( Ambystoma mexicanum ), two salamander species separated by over 100 million years of evolution, use distinct mechanisms to regenerate muscle—namely via dedifferentiation or activation of satellite stem cells, respectively (Sandoval‐Guzmán et al , ). Heart and retina regeneration, which is present in zebrafish ( Danio rerio ) (Poss et al , ; Bernardos et al , ), is absent or impaired in another teleost fish species, the Japanese medaka ( Oryzias latipes ) (Lai et al , ; Lust and Wittbrodt, ). Such examples indicate the importance of studying numerous species to comprehend different strategies that have evolved and could eventually be used to induce regeneration in non‐regenerative species.…”