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K. B. Moore, M. Agathocleous, I. Iordanova, W. A. Harris, M. L. Vetter; Wnt-ß-catenin Signaling Blocks Differentiation of Retinal Progenitors in a Sox2- and Notch-dependent Manner. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4088.
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© ARVO (1962-2015); The Authors (2016-present)
Canonical Wnt signaling is active in the stem cell and progenitor niche in the Xenopus retina, and we have shown that it drives the expression of Sox2, which is required for neurogenesis. However, sustained activation of this pathway prevents retinal neuron differentiation, suggesting that Wnt/ß-catenin signaling may act to maintain retinal progenitors. In this study, we investigate how canonical Wnt signaling prevents retinal progenitor differentiation.
We activated Wnt/ß-catenin signaling in Xenopus retinal progenitors by in vivo lipofection of DNA for stabilized ß-catenin or TCF3-VP16 and assayed for cell type using antibodies and proliferation using BrDU. To define at what step progenitors were blocked in differentiation, we generated transgenic embryos expressing stabilized ß-catenin in retinal progenitors and assayed for gene expression changes by in situ hybridization. mRNAs for Sox2, and dominant-negative Delta were injected into both wild type and transgenic cleavage-stage embryos and changes in gene expression were assayed by in situ hybridization.
Constitutive activation of Wnt/ß-catenin signaling in retinal progenitors maintained them as undifferentiated neuroepithelial cells and promoted their proliferation. Proneural genes were expressed normally, but the expression of proneural target genes and markers of differentiated retinal neurons was reduced. Sox2 failed to be downregulated, and Sox2 overexpression mimicked the effects of Wnt signaling on gene expression. However, proliferation was not increased and the cells differentiated as Müller glia. Inhibition of Notch signaling reversed the ability of both Wnt/ß-catenin and Sox2 to suppress neuronal differentiation.
Wnt/ß-catenin regulates the process of retinal progenitor differentiation via Sox2, but regulates proliferation independent of Sox2. Inhibition of Notch signaling reverses the ability of both Wnt/ß-catenin and Sox2 to block differentiation suggesting that Notch activity downstream of Sox2 is required for canonical Wnt signaling to prevent retinal differentiation.
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