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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.08-109009v1 fj.08-109009v2 22/8/3087    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Mathew, L. K. Articles by Tanguay, R. L. PubMed PubMed Citation Articles by Mathew, L. K. Articles by Tanguay, R. L.

Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish

Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, USA

¹Correspondence: Oregon State University, Department of Environmental and Molecular Toxicology, 1007 ALS, Corvallis, Oregon 97331-7301 USA. E-mail: robert.tanguay{at}oregonstate.edu

Exposure to dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wide array of toxicities in vertebrates, which are mostly considered to be mediated through the inappropriate activation of the aryl hydrocarbon receptor (AHR) signaling pathway. Although transcriptional regulation by AHR is widely studied, the molecular mechanisms responsible for the adverse outcomes after AHR activation are largely unknown. To identify the important downstream events of AHR activation, we employed the zebrafish caudal fin regeneration model, where AHR activation blocks the regenerative process. Comparative toxicogenomic analysis revealed that both adult and larval fins respond to TCDD during regeneration with misexpression of Wnt signaling pathway members and Wnt target genes. R-Spondin1, a novel ligand for the Wnt coreceptor, was highly induced, and we hypothesized that misexpression of R-Spondin1 is necessary for AHR activation to block regeneration. Partial antisense repression of R-Spondin1 reversed the inhibitory effect of TCDD, and tissue regeneration was restored. This finding demonstrates that inhibition of regeneration by TCDD is mediated by misinduction of R-Spondin1. Because R-Spondin1 signals through the Wnt coreceptor LRP6, we further demonstrated that the TCDD-mediated block in regeneration is also LRP6 dependent. Collectively, these results indicate that inappropriate regulation of R-Spondin/LRP6 is absolutely required for TCDD to inhibit fin regeneration.—Mathew, L. K., Sengupta, S. S., LaDu, J., Andreasen, E. A., Tanguay, R. L. Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish.

Key Words: TCDD • dioxin • fin • differentiation • LRP6

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