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Mapping Canonical Wnt Signaling in the Developing and Adult Retina

¹From the Molecular Medicine Program, Ottawa Health Research Institute, and University of Ottawa Eye Institute, Ottawa, Ontario, Canada; the ²Center for Neuromuscular Disease, and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; and the ³McGill University Health Center, Department of Obstetrics and Gynecology, Royal Victoria Hospital, Montreal, Quebec, Canada.

PURPOSE. The role of the Wnt[b]/ß-catenin–dependent pathway (canonical Wnt pathway) in the context of retinal development and homeostasis is largely unknown. This study was undertaken to characterize activation of the Wnt canonical pathway and its relevance to cell type populations in the developing and adult retina.

METHODS. Tissue from TCF/Lef-LacZ (T-cell–specific transcription factor/lymphoid enhancer–binding factor) transgenic mice was used for monitoring the activation of the canonical Wnt pathway. Lithium (Li⁺) treatment was applied to induce ectopic activation of the TCF/Lef-LacZ reporter gene in retinal explants. Gene expression and retinal cell types were examined by in situ hybridization (ISH) or by immunohistochemistry (IHC).

RESULTS. On Li⁺ treatment, ectopic expression of the TCF/Lef-LacZ reporter gene was rapidly and dramatically induced in retinal explants. The pattern of TCF/Lef-LacZ reporter gene expression was dynamic throughout retinal development and in the adult retina. There was a distinctive expression pattern in each cellular layer, in the developing ciliary margin (CM), and the prospective ciliary epithelium. In the mature retina, the TCF/Lef-LacZ reporter gene was expressed in subsets of retinal ganglion cells (RGCs) and amacrine cells. The expression of the four TCF/Lef transcription factors overlapped with activation of the TCF/Lef-LacZ reporter.

CONCLUSIONS. The TCF/Lef-LacZ transgene is a faithful reporter of canonical Wnt signaling in the retina. The pattern of TCF/Lef-LacZ reporter gene activation and of TCF/Lef transcription factor expression suggests that activation of the canonical Wnt pathway is developmental-stage dependent and is spatially modulated. Our findings also imply the involvement of this pathway in the specification and/or generation of ciliary epithelium, cellular differentiation, axon guidance, and connectivity to targets in the central nervous system and in the maintenance or function of specific retinal neurons in the adult.

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