Implications of a Multi-Step Trigger of Retinal Regeneration in the Adult Newt

Abstract

The newt is an amazing four-limbed vertebrate that can regenerate various body parts including the retina. In this animal, when the neural retina (NR) is removed from the eye by surgery (retinectomy), both the NR and the retinal pigment epithelium (RPE) eventually regenerate through the process of reprogramming and proliferation of RPE cells. Thus far, we have pursued the onset mechanism of adult newt retinal regeneration. In this study, using an in vitro system, we found that both mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK and β-catenin were involved in cell cycle re-entry of RPE cells. MEK-ERK signaling activity in RPE cells was strengthened by retinectomy, and nuclear translocation of β-catenin in RPE cells was induced by attenuation of cell–cell contact, which was promoted by incision of the RPE or its treatment with ethylene glycol tetraacetic acid (EGTA). EGTA is a Ca2+ chelator that disrupts cadherin-mediated cell–cell adhesion. Reinforcement of MEK-ERK signaling activity was a prerequisite for nuclear translocation of β-catenin. These results suggest that retinectomy followed by attenuation of cell–cell contact may trigger cell cycle re-entry of RPE cells. This study, together with our previous findings concerning the proliferation and multipotency of adult newt RPE cells, provides insight into the mechanism of the multi-step trigger in which the onset of retinal regeneration in the adult newt is rigorously controlled.

MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration

“…On the other hand, although MAPK/ERK exists ubiquitously in all cells, it is not surprising that the spatio-temporal dynamics of ERK signaling is customized in each organ due to their diverse cell/tissue composition and fluctuates dynamically throughout regeneration processes. As discussed above, sustained ERK activation is observed in salamander myotube turnover [33]; continuous reaction-diffusion trigger waves of ERK activities are evident throughout zebrafish scale regeneration [41]; and a reinforcement of ERK activation is detected following the retinectomy-induced immediate early ERK activation in newt retina regeneration [65]. These particular activation patterns are crucial because short bursts of ERK activation failed to induce mammal myotube regeneration [33], and perturbation of ERK activity waves sabotages proper morphogenesis in zebrafish scale regeneration [41].…”

“…Mammals are susceptible to irreparable degenerative retinal diseases due to their defective eye regeneration capacity [118]. In contrast, amphibians, teleost fish, and avians are able to fully regenerate their damaged retinas [62][63][64][65][66][67][68][69]. Retinal pigmented epithelium cells (RPE) [67,69,119] in newt, Xenopus, and embryonic chicks, and Müller glia cells (MG) [62,63,120,121] in teleost fish, Xenopus, and post-hatched chicks are the major cell sources for retina regeneration through transdifferentiation and proliferation.…”

“…Besides the striking similarity of regeneration strategy employed to regenerate a retina, several studies indicate that ERK is also employed as a key mechanism promoting retina regeneration across species. Through years of work, Chiba's laboratory [64][65][66][67] posits a multi-step mechanism regulating retinal regeneration in the adult newt. Firstly, strong immediate early activation of ERK signaling as well as prominent p-ERK nuclear translocation take place in retinal RPE within 30 min following retinectomy.…”

Potential Endogenous Cell Sources for Retinal Regeneration in Vertebrates and Humans: Progenitor Traits and Specialization

“…The main events on the pathway of this transformation are as follows: the exit of cells from the RPE layer, their proliferation with the loss of the initial phenotypic features, the formation of a population of cells with neuroblast features, and then their differentiation with the recovery to a fully functioning retina ( Figure 6 and Figure 7 ). All these stages are described from the aspect of cell biology and variations in the expression of genes of newt eye RPE cells [ 51 , 52 , 53 , 119 , 120 , 121 , 122 , 123 ].…”

Regenerative medicine in the retina: from stem cells to cell replacement therapy

“…From this point on, intrinsic regeneration upon damage/injury to retinal neurons, glia, or RPE only occurs in lower vertebrates through one of three mechanisms: (1) Cell cycle reentry of Mueller glial cells; 11 , 12 (2) Reactivation of proliferation within RPC in the CMZ 10 or (3) De-differentiation of RPEs into RPCs. 13 – 15 In higher vertebrates, the regenerative potential of MGs appears diminished, and even though recent findings demonstrate that MG-specific overexpression of ASCL1, together with histone deacetylase inhibition, can reinstate their regenerative potential in young mice, 16 the retina of higher vertebrates remains intrinsically vulnerable to disease and injury. Aside from slow, age-related loss of neurons over years, additional stress or insult results in neurodegenerative disorders, including conditions like glaucoma, and age-related macular degeneration (AMD) ( Figure 1 ).…”