Aryl hydrocarbon receptor activation inhibits regenerative growth.

TitleAryl hydrocarbon receptor activation inhibits regenerative growth.
Publication TypeJournal Article
Year of Publication2006
AuthorsMathew, LK, Andreasen, EA, Tanguay, RL
JournalMol Pharmacol
Date Published2006 Jan
KeywordsAnimals, Base Sequence, DNA Primers, Polychlorinated Dibenzodioxins, Receptors, Aryl Hydrocarbon, Regeneration, Reverse Transcriptase Polymerase Chain Reaction, Zebrafish

There is considerable literature supporting the conclusion that inappropriate activation of the aryl hydrocarbon receptor (AHR) alters cellular signaling. We have established previously that fin regeneration is specifically inhibited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in adult zebrafish and have used this in vivo endpoint to evaluate interactions between AHR and growth-controlling pathways. Because there are experimental limitations in studying regeneration in adult animals, we have developed a larval model to evaluate the effect of AHR activation on tissue regeneration. Two-day-old zebrafish regenerate their amputated caudal fins within 3 days. Here, we demonstrate that TCDD specifically blocks regenerative growth in larvae. The AHR pathway in zebrafish is considerably more complex than in mammals, with at least three zebrafish AHR genes (zfAHR1a, zfAHR1b, and zfAHR2) and two ARNT genes (zfARNT1 and zfARNT2). Although it was presumed that the block in regeneration was mediated by AHR activation, it had not been experimentally demonstrated. Using antisense morpholinos and mutant fish lines, we report that zfAHR2 and zfARNT1 are the in vivo dimerization partners that are required for inhibition of regeneration by TCDD. Several pathways including fibroblast growth factor (FGF) signaling are essential for fin regeneration. Even though impaired FGF signaling and TCDD exposure both inhibit fin regeneration, their morphometric response is distinct, suggesting that the mechanisms of impairment are different. With the plethora of molecular and genetic techniques that can be applied to larval-stage embryos, this in vivo regeneration system can be further exploited to understand cross-talk between AHR and other signaling pathways.

Alternate JournalMol. Pharmacol.
PubMed ID16214955
Grant ListES00210 / ES / NIEHS NIH HHS / United States
ES03850 / ES / NIEHS NIH HHS / United States
ES10820 / ES / NIEHS NIH HHS / United States
R01 ES010820 / ES / NIEHS NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States