Downregulation of Otx2 in the dedifferentiated RPE cells of regenerating newt retina

Sakami, Sanae; Hisatomi, Osamu; Sakakibara, Shunsuke; Liu, Janice; Reh, Thomas A.; Tokunaga, Fumio

doi:10.1016/j.devbrainres.2004.11.008

Cited by 38 publications

(24 citation statements)

References 39 publications

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“…As discussed for RPESCs, the process of RPE renewal might not require Pax6 at levels equivalent to those for development of the RPE. Interestingly, a published report indicated that another transcription factor, Otx2, which is required for RPE cell differentiation during eye development, might be involved in the maintenance and specification of RPE cells during retinal regeneration26.…”

Section: Discussionmentioning

confidence: 99%

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

Islam

Nakamura

Casco-Robles

et al. 2014

Sci Rep

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The reprogramming of retinal pigment epithelium (RPE) cells in the adult newt immediately after retinal injury is an area of active research for the study of retinal disorders and regeneration. We demonstrate here that unlike embryonic/larval retinal regeneration, adult newt RPE cells are not directly reprogrammed into retinal stem/progenitor cells; instead, they are programmed into a unique state of multipotency that is similar to the early optic vesicle (embryo) but preserves certain adult characteristics. These cells then differentiate into two populations from which the prospective-neural retina and -RPE layers are formed with the correct polarity. Furthermore, our findings provide insight into the similarity between these unique multipotent cells in newts and those implicated in retinal disorders, such as proliferative vitreoretinopathy, in humans. These findings provide a foundation for biomedical approaches that aim to induce retinal self-regeneration for the treatment of RPE-mediated retinal disorders.

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Section: Discussionmentioning

confidence: 99%

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

Islam

Nakamura

Casco-Robles

et al. 2014

Sci Rep

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“…The pattern of Otx2 expression in the RPE has also been studied in the course of cell conversion during NR regeneration in newts C. pyrrhogaster [19] and Pl. waltl [37].…”

Section: Differentiation Of Newt Rpe Cells and Conditions Of Its Smentioning

confidence: 99%

“…As shown by in situ hybridization, Otx2- expressing cells are evenly distributed all over the RPE layer, both in its central zone (involved in NR regeneration) and the peripheral zone (not involved in it). There is evidence that Otx2 is expressed for 14 days after the initiation of regeneration (NR removal) in approximately half of the RPE cell population, including cells expressing the PCNA proliferation marker [19]. Thus, as in the case of the RPE65 protein, the Otx2 expression in RPE cells is apparently not an obstacle to their entry onto the path of reprogramming.…”

Section: Differentiation Of Newt Rpe Cells and Conditions Of Its Smentioning

confidence: 99%

“…Accumulated data on morphological and molecular features of native retinal pigment epithelium (RPE) cells and those at the beginning of natural reprogramming to neuronal and glial cells of regenerating retina [6,7,11,12,13,14,17,18,19,20,21,22,23,24]. ( A ) RPE cells (thin white arrows) in the RPE layer of the newt Pleurodeles waltl ; ( B ) RPE cell that left its layer and stays at the beginning of reprogramming (thick white arrow); Scale bar: 100 µm.…”

Section: Figurementioning

confidence: 99%

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Cellular and Molecular Preconditions for Retinal Pigment Epithelium (RPE) Natural Reprogramming during Retinal Regeneration in Urodela

Grigoryan

Markitantova

2016

Biomedicines

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Many regeneration processes in animals are based on the phenomenon of cell reprogramming followed by proliferation and differentiation in a different specialization direction. An insight into what makes natural (in vivo) cell reprogramming possible can help to solve a number of biomedical problems. In particular, the first problem is to reveal the intrinsic properties of the cells that are necessary and sufficient for reprogramming; the second, to evaluate these properties and, on this basis, to reveal potential endogenous sources for cell substitution in damaged tissues; and the third, to use the acquired data for developing approaches to in vitro cell reprogramming in order to obtain a cell reserve for damaged tissue repair. Normal cells of the retinal pigment epithelium (RPE) in newts (Urodela) can change their specialization and transform into retinal neurons and ganglion cells (i.e., actualize their retinogenic potential). Therefore, they can serve as a model that provides the possibility to identify factors of the initial competence of vertebrate cells for reprogramming in vivo. This review deals mainly with the endogenous properties of native newt RPE cells themselves and, to a lesser extent, with exogenous mechanisms regulating the process of reprogramming, which are actively discussed.

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“…In chick RPE cultures, overexpression of different pro-neural transcriptional factors such as sox2 , ash1 , ath5 , neuroD , neurogenin1 , neurogenin3 , cath5 and msx2 can promote the transdifferentiation of the RPE into neuronal cells (reviewed in [1]). By contrast, there are several factors associated with RPE specification, including Mitf , Otx2 , Wnt13 , BMP , Shh and Activin [6,8-15]. The inactivation of Wnt/beta-catenin signaling in the embryonic mouse RPE results in down-regulation of RPE-specific factors Mitf and Otx2 and expression of neural retina markers Chx10 and Rx [9,10].…”

Section: Introductionmentioning

confidence: 99%

Reprogramming of the chick retinal pigmented epithelium after retinal injury

et al. 2014

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BackgroundOne of the promises in regenerative medicine is to regenerate or replace damaged tissues. The embryonic chick can regenerate its retina by transdifferentiation of the retinal pigmented epithelium (RPE) and by activation of stem/progenitor cells present in the ciliary margin. These two ways of regeneration occur concomitantly when an external source of fibroblast growth factor 2 (FGF2) is present after injury (retinectomy). During the process of transdifferentiation, the RPE loses its pigmentation and is reprogrammed to become neuroepithelium, which differentiates to reconstitute the different cell types of the neural retina. Somatic mammalian cells can be reprogrammed to become induced pluripotent stem cells by ectopic expression of pluripotency-inducing factors such as Oct4, Sox2, Klf4, c-Myc and in some cases Nanog and Lin-28. However, there is limited information concerning the expression of these factors during natural regenerative processes. Organisms that are able to regenerate their organs could share similar mechanisms and factors with the reprogramming process of somatic cells. Herein, we investigate the expression of pluripotency-inducing factors in the RPE after retinectomy (injury) and during transdifferentiation in the presence of FGF2.ResultsWe present evidence that upon injury, the quiescent (p27Kip1+/BrdU-) RPE cells transiently dedifferentiate and express sox2, c-myc and klf4 along with eye field transcriptional factors and display a differential up-regulation of alternative splice variants of pax6. However, this transient process of dedifferentiation is not sustained unless FGF2 is present. We have identified lin-28 as a downstream target of FGF2 during the process of retina regeneration. Moreover, we show that overexpression of lin-28 after retinectomy was sufficient to induce transdifferentiation of the RPE in the absence of FGF2.ConclusionThese findings delineate in detail the molecular changes that take place in the RPE during the process of transdifferentiation in the embryonic chick, and specifically identify Lin-28 as an important factor in this process. We propose a novel model in which injury signals initiate RPE dedifferentiation, while FGF2 up-regulates Lin-28, allowing for RPE transdifferentiation to proceed.

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Downregulation of Otx2 in the dedifferentiated RPE cells of regenerating newt retina

Cited by 38 publications

References 39 publications

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

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

Cellular and Molecular Preconditions for Retinal Pigment Epithelium (RPE) Natural Reprogramming during Retinal Regeneration in Urodela

Reprogramming of the chick retinal pigmented epithelium after retinal injury

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