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RPE specification in the chick is mediated by surface ectoderm-derived BMP and Wnt signalling

Jörg Steinfeld, Ichie Steinfeld, Nicola Coronato, Meggi-Lee L. Hampel, Paul G. Layer, Masasuke Araki , Astrid Vogel-Höpker.

Development. 2013;140(24):4959-69. 

Fachgebiet Entwicklungsbiologie und Neurogenetik, Technische Universität Darmstadt, Schnittspahnstrasse 13, D-64287 Darmstadt, Germany and

Developmental Neurobiology Laboratory, Faculty of Science, Nara Women´s University, Nara 630-8506, Japan.



The retinal pigment epithelium (RPE) is a single-layered, pigmented tissue that is indespensable for vertebrate eye development and vision. According to a classical model of optic vesicle patterning, the surface ectoderm produces fibroblast growth factors (FGFs) that specify the neuroretina (NR) distally, while members of the TGF-{Beta} family released from the proximally located mesenchyme are involved in RPE specification. However, we previously proposed that BMPs released from the surface ectoderm are essential for RPE specification in the chick (Müller et al., 2007; Development 134, 3483-3493). We now show that the Bmp– and Wnt-expressing surface ectoderm is required for RPE specification. Our study reveals that Wnt signalling from the overlying surface ectoderm is involved in restricting BMP-mediated RPE specification to the dorsal optic vesicle. Wnt2b is expressed in the dorsal surface ectoderm and subsequently in dorsal optic vesicle cells. Activation of the Wnt signalling pathway by either implanting Wnt3a-soaked beads or by inhibiting GSK-3{Beta} at optic vesicle stages inhibits NR development and converts the entire optic vesicle into RPE. Surface ectoderm removal at early optic vesicle stages or inhibition of Wnt signalling, but not Wnt/{Beta}-catenin signalling, prevents pigmentation and results in downregulation of the RPE regulatory gene Microphthalmia-associated transcription factor (Mitf). Activation of the BMP or Wnt signalling pathway can replace the surface ectoderm to rescue MITF expression and optic cup formation. We further provide evidence that BMPs and Wnts cooperate, via a GSK-3{Beta}-dependent but {Beta}-catenin-independent pathway, at the level of pSmad to ensure RPE specification in dorsal optic vesicle cells. Based on these results, we propose a new dorso-ventral model of optic vesicle patterning, whereby initially surface ectoderm-derived Wnt signalling directs dorsal optic vesicle cells to develop into RPE through a stabilising effect of BMP signalling. These findings potentially provide the basis for the development of novel therapeutic approaches for the treatment of major blinding diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa.



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Figure legend:

Dorso-ventral model of optic vesicle patterning in the chick embryo, integrating BMP and Wnt actions. This model suggests that at stage 9 (A), BMPs released from the surface ectoderm initiate RPE specification through phosphorylation of Smad-1, -5 and/or -8 (Smad-P), which leads to Mitf expression in distal optic vesicle cells. (B) At stage 10, Wnt signalling from the dorsal surface ectoderm inhibits GSK-3{Beta} which in turn stabilises BMP signalling. The transcription factor Smad-P can translocate to the nucleus to initiate Mitf expression, thereby directing dorsal optic vesicle cells towards an epithelial cell fate (RPE). In the absence of Wnt ligands within the ventral surface ectoderm, Smad is triple phosphorylated by BMPs released from the surface ectoderm, by GSK-3{Beta} (not inhibited by Wnts) and possibly by FGF signalling (not studied here). This results in proteasomal degradation of pSmad in the ventral optic vesicle. The inhibition of BMP signalling now allows FGF/MAPK signalling to induce Vsx2 expression, thereby directing the ventral region of the optic vesicle towards a neuronal cell fate.

RPE specification chick is mediated by surface ectoderm-derived BMP and Wnt signalling.- Global Medical Discovery