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C. B. Stevens, S. Hunter, D. Stenkamp; Interactions Between Retinoic Acid and Wnt Signaling During Photoreceptor Development in Zebrafish. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5931.
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The absence of retinoic acid (RA) or its precursor Vitamin A leads to defects in the development of the retina and degeneration of the photoreceptors. The addition of RA during retinal neurogenesis can alter the development of photoreceptor progenitors. Analysis of eye-specific microarray data from zebrafish embryos treated with RA suggests RA and wnt signaling pathways interact during photoreceptor development. This connection was examined further using transgenic lines to study wnt signaling in zebrafish.
For the microarray analysis three sets of zebrafish embryos were divided into control (Dimethylsulfoxide) and experimental (0.3 µM RA) groups. Embryos were treated during the period of photoreceptor differentiation and eyes removed for RNA extraction followed by hybridization to Affymetrix zebrafish gene chips. Tg(hsp70l:dkk1-GFP)w32 embryos, which overexpress the wnt inhibitor dkk1 in response to heat shock, were used to achieve in vivo loss of wnt signaling during retinal development.
Microarray analysis revealed a large list of transcription factors, cell signaling molecules, and extracellular matrix and cytoskeletal molecules that were up- or downregulated by RA. Upregulated genes included hox genes, and the wnt signaling related genes sfrp1a and wnt11. Downregulated genes included wnt receptors fz9 and fzb, and wnt signaling inhibitors dkk1 and sponb2. Heat shocked Tg(hsp70l:dkk1-GFP)w32 embryos displayed a significant reduction in expression of rod and cone photoreceptor markers in addition to reduced eye size. RA treatment of Tg(TOP:GFP)w25 embryos, a reporter line for wnt/beta-catenin signaling, did not cause a detectable change in reporter expression.
The microarray analysis suggests complex reciprocal interactions exist between RA and wnt signaling during photoreceptor development. The results from overexpressing dkk1 suggest that blocking signaling through extracellular wnt proteins has a significant effect on photoreceptor development. However, the specific wnt signaling pathway modified by RA in the retina remains to be determined.
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