The newt reprograms mature RPE cells into a unique multipotent state for retinal regeneration

Islam, Md. Rafiqul; Nakamura, Kenta; Casco-Robles, Martin Miguel; Kunahong, Ailidana; Inami, Wataru; Toyama, Fubito; Maruo, Fumiaki; Chiba, Chikafumi

doi:10.1038/srep06043

Cited by 50 publications

(98 citation statements)

References 25 publications

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“…Figure 5A illustrates a summary of events that take place during retinal regeneration [3,10]. In both intact RPE cells and RPE cells immediately after retinectomy (day 0), β-catenin was mostly localized on the cell membrane along the region of cell–cell contact where N-cadherin was co-localized (compare Figure 5B,C with Figure 6A,B).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

“…Reprogramming RPE cells, i.e., RPESCs, newly express transcription factors Mitf and Pax6 as well as pluripotency factors such as Sox2, c-Myc and Klf4 [3]. As mentioned above, Pax6 is a key factor for RPESCs to direct their fate from myofibroblast-like cells to retinal regeneration [4].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Taken together, our results suggest that the intact adult newt RPE cells are not comparable to either immature/uncommitted state of RPE cells or retinal stem/progenitor cells, as well as a possibility of reprogramming of RPE cells into such multipotent cells upon retinectomy. On the next stage of this study, we must carry out immunohistochemistry and single-cell qPCR to address the expression of these factors in the RPE-derived cells at Stage E-1 (our study on this subject was published [29] while the current article was under review).…”

Section: Resultsmentioning

confidence: 99%

A Transcriptome for the Study of Early Processes of Retinal Regeneration in the Adult Newt, Cynops pyrrhogaster

et al. 2014

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Retinal regeneration in the adult newt is a useful system to uncover essential mechanisms underlying the regeneration of body parts of this animal as well as to find clues to treat retinal disorders such as proliferative vitreoretinopathy. Here, to facilitate the study of early processes of retinal regeneration, we provide a de novo assembly transcriptome and inferred proteome of the Japanese fire bellied newt (Cynops pyrrhogaster), which was obtained from eyeball samples of day 0–14 after surgical removal of the lens and neural retina. This transcriptome (237,120 in silico transcripts) contains most information of cDNAs/ESTs which has been reported in newts (C. pyrrhogaster, Pleurodeles waltl and Notophthalmus viridescence) thus far. On the other hand, de novo assembly transcriptomes reported lately for N. viridescence only covered 16–31% of this transcriptome, suggesting that most constituents of this transcriptome are specific to the regenerating eye tissues of C. pyrrhogaster. A total of 87,102 in silico transcripts of this transcriptome were functionally annotated. Coding sequence prediction in combination with functional annotation revealed that 76,968 in silico transcripts encode protein/peptides recorded in public databases so far, whereas 17,316 might be unique. qPCR and Sanger sequencing demonstrated that this transcriptome contains much information pertaining to genes that are regulated in association with cell reprogramming, cell-cycle re-entry/proliferation, and tissue patterning in an early phase of retinal regeneration. This data also provides important insight for further investigations addressing cellular mechanisms and molecular networks underlying retinal regeneration as well as differences between retinal regeneration and disorders. This transcriptome can be applied to ensuing comprehensive gene screening steps, providing candidate genes, regardless of whether annotated or unique, to uncover essential mechanisms underlying early processes of retinal regeneration.

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“…RNA-seq data by de novo transcriptome assembly of complement DNA from testes was constructed with the large aid of Dr. F. Toyama of Utsunomiya University and Dr. C. Chiba of University of Tsukuba [ 33 ]. Total RNA was purified from the spermatogenic testes by Trizol reagent (Life Technologies, Tokyo, Japan) and evaluated with an Agilent 2100 Bioanalyzer (Agilent Technology, Santa Clara, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Sperm Proteases that May Be Involved in the Initiation of Sperm Motility in the Newt, Cynops pyrrhogaster

Sano

Shibata

Sugiyama

et al. 2014

IJMS

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A protease of sperm in the newt Cynops pyrrhogaster that is released after the acrosome reaction (AR) is proposed to lyse the sheet structure on the outer surface of egg jelly and release sperm motility-initiating substance (SMIS). Here, we found that protease activity in the sperm head was potent to widely digest substrates beneath the sperm. The protease activity measured by fluorescein thiocarbamoyl-casein digestion was detected in the supernatant of the sperm after the AR and the activity was inhibited by 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), an inhibitor for serine or cysteine protease, suggesting the release of serine and/or cysteine proteases by AR. In an in silico analysis of the testes, acrosins and 20S proteasome were identified as possible candidates of the acrosomal proteases. We also detected another AEBSF-sensitive protease activity on the sperm surface. Fluorescence staining with AlexaFluor 488-labeled AEBSF revealed a cysteine protease in the principal piece; it is localized in the joint region between the axial rod and undulating membrane, which includes an axoneme and produces powerful undulation of the membrane for forward sperm motility. These results indicate that AEBSF-sensitive proteases in the acrosome and principal piece may participate in the initiation of sperm motility on the surface of egg jelly.

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The newt reprograms mature RPE cells into a unique multipotent state for retinal regeneration

Cited by 50 publications

References 25 publications

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

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

A Transcriptome for the Study of Early Processes of Retinal Regeneration in the Adult Newt, Cynops pyrrhogaster

Sperm Proteases that May Be Involved in the Initiation of Sperm Motility in the Newt, Cynops pyrrhogaster

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