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S. Xu, T. Holowacz, T. Berg, J.–C. Ren, M. Taketo, J. Huelsken, D. van der Kooy; The Role of ß–Catenin in Retinal Stem Cells and Retinal Development . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4200.
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© ARVO (1962-2015); The Authors (2016-present)
Adult mammalian retinal stem cells (RSCs) reside in the pigmented ciliary epithelia. The molecular mechanisms underlying the generation, proliferation and differentiation of RSCs are largely unknown. The purpose of this study is to investigate the role(s) of the canonical Wnt/ß–catenin pathway in RSCs and retinal development.
We created two retinal specific ß–catenin mutant mouse models: 1) retinal specific ß–catenin knockout, α–Cre, ß–cateninflox/flox, was created by breeding α–Cre mice, in which the expression of Cre recombinase is under the peripheral retinal specific promoter, α promoter from Pax6 gene (Marquardt et al. 2001), with ß–cateninflox mice, in which two loxP sites flank exons 2 and 6 (Huelsken et al. 2001); 2) α–Cre, Catnblox(ex3), a dominant gain–of–function mutant with a retinal specific expression of a dominant stable form of ß–catenin by breeding α–Cre transgenic mice with Catnblox(ex3) mice, in which two loxP sites flank exon 3 of ß–catenin (Harada et al. 1999). Cre–mediated recombination results in the deletion of multiple serine/threonine residues encoded by exon 3 that are phosphorylated by glycogen synthase kinase (GSK) 3ß.
Our preliminary studies showed that: 1) the dominant gain–of–function mutation results in small eyes; 2) The retinas are highly disorganized with multiple rosettes in both the knockout and the gain–of–function mutant; 3) in adult animals, conditional knockout of ß–catenin results in 68–91% decrease of the number of RSCs in the ciliary epithelia as assayed by the formation of RSC spheres.
Our data suggests that the canonical Wnt/ß–catenin pathway may play important role(s) in retinal stem and/or progenitor cells and is important for the normal structural organization of the retina. Further studies are ongoing to elucidate the detailed mechanisms.
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