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Abstract

The continuous life-long growth of the fish retina is fuelled by neural stem cells located within the ciliary marginal zone (CMZ). These stem cells are characterised by their multipotency and ability to self-renew. Through asymmetric divisions, the neural stem cells give rise to progenitor cells with restricted proliferation potential that ultimately commit to terminally differentiated neurons of the mature retina. In this process, pharmacological manipulation suggests that Wnt signalling acts on both cell proliferation and differentiation, but a refined analysis is missing. Therefore, I present here a detailed analysis of Wnt signalling localisation and function within different cell types and their lineages in the post-embryonic CMZ of medaka. In this thesis, I show that Wnt ligands are expressed by cells of the retinal pigment epithelium, which is located directly adjacent to the CMZ. Wnt/β-catenin signalling activity is restricted to stem cells, whereas β-catenin independent Wnt/LRP6 signalling extends to dividing progenitor cells. To address the role of Wnt signalling in proliferation and differentiation of specific stem and progenitor cells, I created transgenic lines that allow inducible clonal labelling combined with upregulation of Wnt signalling in individual cells. My lineage tracing experiments suggest that Wnt upregulation has diverging effects on stem and progenitor cells. First, stem cells lose stemness characteristics presumably through induction of apoptosis or symmetric division. Second, progenitor cells reacquire the capacity to self-renew, but their pre-existing fate restrictions are irreversible. Finally, committed progenitors shift their fate and/or change their division mode and proliferation characteristics upon Wnt upregulation. Taken together, my results indicate that Wnt signalling functionally divides the CMZ into stem cells, non-committed and committed progenitors, which has far reaching implications for Wnt functions in other stem cell niches.