The mammalian aryl hydrocarbon receptor mediates the toxic effects
Dioxins and related manmade pollutants are important hazards to human
and animal health. People exposed to dioxin often have a skin condition
called chloracne, and experiments in animal model systems suggest
that dioxin exposure can also cause birth defects, cancer, and neurological
defects. The toxic effects of dioxin are mediated by the aryl hydrocarbon
receptor (AHR). Dioxin binds to AHR, causing misregulation of this
C. elegans is a powerful genetic model system. The adults
are approximately one millimeter long, and they eat bacteria. C.
elegans are transparent. The wild-type embryonic and postembryonic
lineages have been extensively documented and are essentially invariant.
The nervous system consists of 302 neurons of at least 118 subtypes,
and the neuronal connections have been reconstructed from serial section
electron micrographs (www.wormatlas.org).
These resources enable researchers to diagnose mutant phenotypes at
the level of individual cells. The sequence of the genome is known
(www.wormbase.org), and large-scale
studies are underway to characterize the function of every gene by
double-stranded RNA interference, full-genome microarrays, and semi-automated
analyses of protein-protein interactions.
signaling in C. elegans
The C. elegans orthologs of AHR and it’s dimerization partners
are encoded by the genes ahr-1 and aha-1, respectively.
The gene products, AHR-1 and AHA-1, share important biochemical properties
with their mammalian cognates. There are also interesting differences.
Like other invertebrate AHR homologs that have been tested, C.
elegans AHR-1 does not bind radiolabeled derivatives of TCDD
or beta-naphthoflavone. This suggests that evolutionary divergent
AHR proteins recognize different spectrums of ligands or have varying
mechanisms of activation.
Powell-Coffman, Bradfield, and Wood (1998) PNAS 95, 2844
C. elegans ahr-1
is required for normal neuronal development.
ahr-1:GFP reporters are expressed in a subset of neurons. Animals
lacking ahr-1 function have specific defects in neuronal differentiation,
as evidenced by changes in gene expression, aberrant cell migration,
axon branching, or supernumerary neuronal processes. These data, when
considered with the neurotoxic effects of AHR-activating pollutants,
support the hypothesis that AHR has an evolutionarily conserved role
in neuronal development.
and Powell-Coffman (2004) Dev. Biol. 270, 64
The C. elegans
AHR-1 transcription complex regulates aggregation behavior.
Behavioral defects are evident in C. elegans lacking
ahr-1. Some strains of C. elegans aggregate on lawns
of bacterial food. This behavior is modulated by nutritional cues
and ambient oxygen levels, and aggregation is inhibited by the npr-1
G protein-coupled neuropeptide receptor gene. We discovered that loss-of-function
mutations in ahr-1 or its transcription partner aha-1 (ARNT) suppressed
aggregation behavior in npr-1-deficient animals. This behavioral defect
was not irreparable. Aggregation behavior could be restored to ahr-1-deficient
animals by heat-shock induction of ahr-1 expression in larvae. Our
data support a model in which the AHR-1:AHA-1 transcription complex
regulates the expression of soluble guanylate cyclase genes and other
unidentified genes that are essential for acute regulation of aggregation
Qin, Zhai, and Powell-Coffman (2006) Dev. Biol. 298, 606