Abstract
In the present study we explored the role of β-catenin in mediating chick retina regeneration. The chick can regenerate its retina by activating stem/progenitor cells present in the ciliary margin (CM) of the eye or via transdifferentiation of the retinal pigmented epithelium (RPE). Both modes require fibroblast growth factor 2 (FGF2). We observed, by immunohistochemistry, dynamic changes of nuclear β-catenin in the CM and RPE after injury (retinectomy). β-catenin nuclear accumulation was transiently lost in cells of the CM in response to injury alone, while the loss of nuclear β-catenin was maintained as long as FGF2 was present. However, nuclear β-catenin positive cells remained in the RPE in response to injury and were BrdU-/p27+, suggesting that nuclear β-catenin prevents those cells from entering the cell cycle. If FGF2 is present, the RPE undergoes dedifferentiation and proliferation concomitant with loss of nuclear β-catenin. Moreover, retinectomy followed by disruption of active β-catenin by using a signaling inhibitor (XAV939) or over-expressing a dominant negative form of Lef-1 induces regeneration from both the CM and RPE in the absence of FGF2. Our results imply that β-catenin protects cells of the CM and RPE from entering the cell cycle in the developing eye, and specifically for the RPE during injury. Thus inactivation of β-catenin is a pre-requisite for chick retina regeneration.
Highlights
Retina regeneration studies have been conducted in different animal models for many years, the molecular mechanism underlying regeneration via different cellular sources is still under rigorous investigation [1,2,3,4,5]
At E4 (HH Stage 24; stage at which retinectomies are performed for regeneration studies), nuclear b-catenin immunoreactivity was detected in a subpopulation of cells in the ciliary margin (CM) including the non-pigmented epithelium (NPE) connected to the retina posteriorly, and the pigmented epithelium (PE) connected to the retinal pigmented epithelium (RPE) posteriorly (Fig. 1H, I)
The nuclear b-catenin+ NPE cells extended to the optic cup lip (OCL), the most anterior domain of the CM that has been reported to house multipotent optic cup stem/progenitor cells including ones for the retina [37,38]
Summary
Retina regeneration studies have been conducted in different animal models for many years, the molecular mechanism underlying regeneration via different cellular sources is still under rigorous investigation [1,2,3,4,5]. The embryonic chick can regenerate its retina via two different mechanisms: by the activation of stem/ progenitor cells present in the CM and by RPE transdifferentiation. It has been shown that in chick neural cells, phosphorylation of b-catenin at tyrosine 489 (Y489) targets it to the nucleus where it binds to its partner(s) TCF/Lef and acts as a co-activator of transcription [24]. In this complex, b-catenin functions as a transcriptional coactivator to facilitate the binding of the complex to chromatin and to recruit components to promote chromatin remodeling [25,26]. That blocking the transcriptional activity of b-catenin is a necessary step in retina regeneration
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