Canonical Wnt Signaling Controls Proliferation of Retinal Stem/progenitor Cells in Post-embryonic Xenopus Eyes.
Résumé
Vertebrate retinal stem cells, which reside quiescently within the ciliary margin, may offer a possibility for treatment of degenerative retinopathies. The highly proliferative retinal precursor cells in Xenopus eyes are confined to the most peripheral region, called the ciliary marginal zone (CMZ). While the canonical Wnt pathway has been implicated in the developing retina of different species, little is known about its involvement in post-embryonic retinas. Using a GFP-based Wnt-responsive reporter, we show that in transgenic Xenopus tadpoles the canonical Wnt signaling is activated in the post-embryonic CMZ. To further investigate the functional implications of this, we generated transgenic, hormone-inducible canonical Wnt pathway activating and repressing systems, which are directed to specifically intersect at the nuclear endpoint of transcriptional Wnt target gene activation. We found that post-embryonic induction of the canonical Wnt pathway in transgenic retinas resulted in increased proliferation in the CMZ compartment. This is most likely due to delayed cell cycle exit, as inferred from a pulse chase experiment on BrdU labeled retinal precursors. Conversely, repression of the canonical Wnt pathway inhibited proliferation of CMZ cells. Neither activation nor repression of the Wnt pathway affected the differentiated cells in the central retina. We conclude that even at post-embryonic stages the canonical Wnt signaling pathway continues to have a major function in promoting proliferation and maintaining retinal stem cells. These findings may contribute to the eventual design of vertebrate, stem cell-based retinal therapies. ______________________________________________________________________________ Author contributions: T.Denayer: Conception and design, manuscript writing, collection and/or assembly of data, data analysis and interpretation; M.L.: Conception and design, collection and/or assembly of data, data analysis and interpretation; C.B.: Collection and/or assembly of data, data analysis and interpretation; T.Deroo: Generation of specific plasmid constructs; S.J.: Collection and/or assembly of data; A.H.: Generation of specific plasmid constructs; F.V.R.: Financial support; M.P.: Conception and design, manuscript writing, collection and/or assembly of data, data analysis and interpretation, final approval of manuscript, financial support; K.V.: Conception and design, manuscript writing, data analysis and interpretation, final approval of manuscript, financial support. Tinneke Denayer and Morgane Locker contributed equally to this work.