Abstract
ABSTRACTIn vertebrates, the retinal pigment epithelium (RPE) and photoreceptors of the neural retina (NR) comprise a functional unit required for vision. During vertebrate eye development, a conversion of the RPE into NR can be induced by growth factors in vivo at optic cup stages, but the reverse process, the conversion of NR tissue into RPE, has not been reported. Here, we show that bone morphogenetic protein (BMP) signalling can reprogram the NR into RPE at optic cup stages in chick. Shortly after BMP application, expression of Microphthalmia-associated transcription factor (Mitf) is induced in the NR and selective cell death on the basal side of the NR induces an RPE-like morphology. The newly induced RPE differentiates and expresses Melanosomalmatrix protein 115 (Mmp115) and RPE65. BMP-induced Wnt2b expression is observed in regions of the NR that become pigmented. Loss of function studies show that conversion of the NR into RPE requires both BMP and Wnt signalling. Simultaneous to the appearance of ectopic RPE tissue, BMP application reprogrammed the proximal RPE into multi-layered retinal tissue. The newly induced NR expresses visual segment homeobox-containing gene (Vsx2), and the ganglion and photoreceptor cell markers Brn3α and Visinin are detected. Our results show that high BMP concentrations are required to induce the conversion of NR into RPE, while low BMP concentrations can still induce transdifferentiation of the RPE into NR. This knowledge may contribute to the development of efficient standardized protocols for RPE and NR generation for cell replacement therapies.
Highlights
In vertebrates, the retinal pigment epithelium (RPE) is a single-layered pigmented epithelium supports metabolic and cellular processes of the light-sensitive photoreceptors located in the multi-layered neural retina (NR)
Bmp5 is expressed in the developing RPE and in surrounding tissues at optic cup stages The dynamic expression pattern of Bmp2, -4 and -7 has been extensively analysed during mouse and chick optic vesicle and cup stages (Fig. S1; see discussion)
We identified BMP5 as another potential signal being involved in RPE development at optic cup stages during vertebrate eye development
Summary
The retinal pigment epithelium (RPE) is a single-layered pigmented epithelium supports metabolic and cellular processes of the light-sensitive photoreceptors located in the multi-layered NR (reviewed in Strauss, 2005; 2011). The RPE exerts important roles during eye development. Isolated RPE cells from the eye periphery of the E5 chick embryo supported in vitro formation of completely laminated 3D retinal spheroids, establishing that retinal tissue can be produced in vitro by self-organisational processes recapitulating normal retinogenesis (Willbold and Layer, 1989, 1994; Layer et al, 2001). Pluripotent stem cells, i.e. embryonic stem cells or induced pluripotent stem cells are used to recapitulate normal developmental processes to generate RPE and NR Recently an efficient method for deriving a functional RPE cell population from both human embryonic and induced pluripotent stem cells has been described. Nutrition has been shown to play an important role in preventing blindness in patients with age-related macular degeneration (reviewed in Campbell and Campbell, 2004)
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