Aryl Hydrocarbon Receptor Activation Inhibits Regenerative Growth
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...
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Published in | Molecular pharmacology Vol. 69; no. 1; pp. 257 - 265 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.01.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.105.018044 |