1 Department of Molecular, Cellular and Developmental Biology, Sinsheimer
Laboratories, Howard Hughes Medical Institute, University of California, Santa
Cruz, CA 95064, USA
2 Department of Genetics, Development, and Cell Biology, Iowa State University,
Ames, IA 50011-3260, USA
Author for correspondence (e-mail:
jin{at}biology.ucsc.edu)
Accepted 31 October 2003
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SUMMARY |
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Key words: Aryl hydrocarbon receptor (AHR-1), ARNT (AHA-1), HSP90, Neuron, GABA, Cell fate, C. elegans
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Introduction |
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Invertebrates generally do not have a dioxin-induced toxic response, and
none of the invertebrate AHRs tested bind dioxin, leading to the hypothesis
that the ancestral role of the AHR family is not in toxin response
(Hahn et al., 1997;
Hahn, 2002
). Studies in
Drosophila have supported this idea. Mutations in the
Drosophila AHR spineless cause reduced sensory bristles and
transformation of distal antenna into distal leg
(Duncan et al., 1998
). This
function of Spineless requires Tango, the Drosophila ARNT
(Emmons et al., 1999
).
Spineless and Tango bind directly and exhibit genetic interactions. Both
Spineless and Tango are normally localized in the nucleus, and, interestingly,
the nuclear localization of Tango depends on Spineless.
ahr-1 and aha-1 are the C. elegans homologs of
AHR and ARNT, respectively (Powell-Coffman
et al., 1998). AHR-1 and AHA-1 bind each other in vitro and can
bind XREs in a sequence specific manner in vitro. AHR-1 can also bind rabbit
HSP90, but not mammalian XAP2
(Powell-Coffman et al., 1998
;
Bell and Poland, 2000
). A
single ortholog of HSP90 in C. elegans is encoded by the
daf-21 gene (Birnby et al.,
2000
). The null mutation of daf-21 is early larval
lethal, and an unusual mutation of daf-21(p673) causes constitutive
formation of dauer larvae.
The C. elegans nervous system is composed of 302 neurons
(White et al., 1986), 26 of
which use
-amino butyric acid (GABA) as the neurotransmitter and
regulate body movement, defecation and foraging behaviors
(McIntire et al., 1993
). These
GABAergic neurons fall into at least five types based on morphology and
function, including the 19 type D ventral cord motor neurons, RIS, AVL, DVB
and four RME neurons. The UNC-30 homeodomain protein controls the
specification of the type D ventral cord neurons
(Jin et al., 1994
). The LIM-6
homeodomain protein regulates subsets of the differentiated aspects of RIS,
AVL and DVB neurons (Hobert et al.,
1999
). The four RME neurons innervate head muscles to control
foraging behavior (White et al.,
1986
; McIntire et al.,
1993
). Although sharing similar neurotransmitter specificity and
the same synaptic targets, the RME neurons can be further divided into two
subgroups, based on cell lineage and gene expression. For example, RMEL and
RMER are lineally related, and express lim-6 and the AMPA-type
glutamate receptor glr-1 (Hart et
al., 1995
). RMED and RMEV do not express these markers; instead
they express the ivermectin receptor avr-15
(Dent et al., 1997
). We found
that loss of function in ahr-1 transforms RMEL/RMER neurons into
RMED/RMEV-like cells. Ectopic expression of AHR-1 in RMED/RMEV can transform
them to an RMEL/RMER-like fate. We provide additional evidence that supports
an evolutionarily conserved partnership of AHR and ARNT. Our findings are
consistent with the notion that an ancestral role of AHR proteins is in
regulating cellular development.
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Materials and methods |
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Isolation and mapping of ju145
juIs76(Punc-25GFP) animals were mutagenized
with ethyl methanesulfonate (EMS) following the standard procedure as
described (Sulston and Hodgkin,
1988). The cell morphology of RME neurons of mutagenized F2
progeny was examined under a Nomarski fluorescence microscope, and mutant
animals were recovered to produce progeny. A total of
6,200 mutagenized
haploid genomes were screened. The ju145 mutation was outcrossed
multiple times before further analysis. Homozygous ju145 mutant
animals exhibited no discernable abnormalities in locomotion, egg laying, or
male mating. The foraging behaviors of ahr-1 animals were observed in
parallel with N2, juIs76, glr-1(n2461), unc-25(e156) and
unc-47(e542) animals on matched L4 and young adult animals, and the
genotypes were blinded. ju145 was mapped to chromosome I because of
its linkage to dpy-5. It was further mapped to the unc-29
dpy-24 interval, near the hP6 marker, based on the following
data: from ju145/unc-29 hP6 dpy-24 heterozygous animals, 8 out of 37
Unc non-Dpy recombinants, and 5 out of 8 Dpy non-Unc animals, segregated
ju145; 0 out of 8 Unc ju145 non-Dpy, and 0 out of 5 Dpy
ju145 non-Unc, segregated hP6. ju145 was uncovered by the
deficiencies qDf7, qDf9 and mnDf111, but not by dxDf1,
dxDf2, eDf3, nDf23, nDf29 or qDf5.
Molecular biology
Cosmids were obtained from the Sanger Centre, Hinxton, UK. DNA preparation
and subcloning followed standard procedures
(Sambrook et al., 1989). The
ahr-1 minimal rescuing construct (pCZ466) was generated by cloning a
10 kb ApaI-SpeI genomic fragment into pSL1190. To make the
pHT101 Pahr-1GFP plasmid, a 5377 bp HindIII-BamHI
genomic fragment, which includes over 3 kb of sequence 5' to the
translational start codon, exon1, intron 1 and part of exon 2, was ligated
into the corresponding sites of the pPD95.67 GFP expression vector (a gift of
A. Fire). To generate Punc-25AHR-1, the ahr-1
promoter was replaced by the unc-25 promoter at the BstBI
site, which is located 14 bp 5' to the start ATG codon of C41G7.5/AHR-1.
Germline transformation was performed following standard procedures
(Mello et al., 1991
). The
co-injection marker was the dominant pRF4 rol-6(su1006) injected at
20 ng/µl. Over 10 transgenic lines expressing
Punc-25AHR-1 were obtained, and all showed similar
effects. juEx467(Punc-25AHR-1) was chosen for
further analysis.
To identify the lesions in ju145, the genomic DNA, including all exons and exon-intron junctions, was amplified from mutant and wild-type animals. DNA sequences were determined using 33P-labeled primers and the fmol sequencing kit (Promega), and were confirmed on both strands and from DNA prepared in independent PCRs.
GABA antibody staining and GFP phenotypic analysis
Anti-GABA staining was performed using the glutaraldehyde-paraformaldehyde
fixation procedure described by McIntire et al.
(McIntire et al., 1992). GFP
reporter expression was directly observed under a 63x objective of a
Zeiss Axioskop fluorescence microscope equipped with a HQ-FITC filter
(Chroma). Images were captured using an AxioCam camera (Zeiss) and analysed
using the Axiovision software (Zeiss).
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Results |
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To address whether AHA-1 is required for AHR-1 function in RMEL/R cell fate specification, we introduced Punc-25GFP into aha-1(ia1) mutants that are viable because of the pharyngeal expression of aha-1. We found that aha-1(ia1) animals showed identical RMEL/R cell morphology phenotypes to ahr-1(ju145) (Fig. 6C, Table 1), indicating that aha-1 is required for RMEL/R cell fate. Furthermore, when we introduced into aha-1(ia1) mutants the juEx467 transgene that expresses ahr-1 ectopically in RMED/V cells, the RMED/V cells did not show inhibition of the longitudinal process extension (Fig. 6G,H; Table 1), supporting the conclusion that aha-1 is required for the effect of ectopic ahr-1.
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ahr-1, ceh-10 and lim-4 function independently to control RME neuron fate
The four RME neurons are closely related neurons by function and
neurotransmitter specificity. The data presented above show that
ahr-1 regulates the cellular differentiation, but not GABA
expression, of RMEL and RMER neurons. lim-6 is expressed in RMEL,
RMER and three other GABA neurons, and has been shown to partially regulate
the expression of unc-25 in AVL, DVB and RIS, but has no effect on
RMEL/R (Hobert et al., 1999).
To address whether ahr-1 might function together with lim-6
to control GABA expression, we made ahr-1(ju145); lim-6(nr2073)
double mutants. These double mutants expressed Punc-25GFP
and Punc-47GFP normally (data not shown). This
observation, together with that that ahr-1 regulates lim-6
expression (Figs 3,
5), suggests that
lim-6 acts downstream of ahr-1, and mediates other functions
of ahr-1 in RMEL/R neurons.
Two transcription factors have been reported to be differentially expressed
in RMED and RMEV neurons. ceh-10 is expressed in RMED, and in
ceh-10 mutants RMED does not express GABA
(Forrester et al., 1998).
lim-4 is expressed in RMEL
(Sagasti et al., 1999
). In a
lim-4 mutant, RMEL expresses GABA and has normal morphology
(Fig. 7B, and data not shown).
As ectopic expression of ahr-1 is able to cause RMED/V neurons to
adopt an RMEL/R-like fate, we addressed whether ceh-10 and
lim-4 might repress the expression of ahr-1 in RMED/V
neurons. A functional AHR-1::GFP is expressed in the nuclei of a selected
group of neurons including RMEL/R (H. Qin and J.A.P.-C., unpublished). We
found that the expression of an integrated transgene expressing AHR-1::GFP was
unaffected in ceh-10(ct78) and lim-4(ky403) animals
(Fig. 7A). We further
investigated how ahr-1 might interact with ceh-10 or
lim-4 by examining the RME neurons in pair-wise double mutants
(Fig. 7B). We found that double
mutants of ahr-1(ju145); ceh-10(ct78) showed an additive phenotype
such that RMEL/R displayed ectopic nerve processes and RMED frequently failed
to express Punc-25GFP to the same degree as
ceh-10(ct78) alone. Double mutants of ahr-1(ju145);
lim-4(ky403) exhibited only RMEL/R defects as did ahr-1(ju145)
alone. Furthermore, in ceh-10(ct78); lim-4(ky403) double mutants,
RMEV was normal, and RMED frequently failed to express
Punc-25GFP as did ceh-10 alone. Thus, these
observations are consistent with a conclusion that ahr-1, ceh-10 and
lim-4 function independently of each other to control the development
or function of the four RME neurons.
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Discussion |
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This function of AHR-1 requires its co-factor AHA-1. aha-1 is
ubiquitously expressed (Jiang et al.,
2001). We find that loss of function in aha-1 causes
morphological defects in RMEL/R neurons identical to those in ahr-1
mutants, and that the ectopic effect of ahr-1 requires
aha-1. An independent study has found that several ahr-1
expressing neurons exhibit aberrant cell morphology and cell migration defects
in ahr-1 mutants (H. Qin and J.A.P.-C., unpublished data). Thus, it
is the cell-type-specific expression of ahr-1 that allows the
AHR-1/AHA-1 heterodimer to exert specific effects on neuronal
differentiation.
GABAergic neuron fate specification in C. elegans involves multiple cellular determinants and signaling pathways
The twenty-six GABAergic neurons in C. elegans fall into five
classes based on morphology and function
(McIntire et al., 1993). The
data presented here, together with previous published reports
(Jin et al., 1994
;
Forrester et al., 1998
;
Hobert et al., 1999
), classify
them into additional subtypes and reveals different themes of regulatory
network underlying the specification of each subtype. The ventral cord type D
motor neurons are related in cell lineage, morphology and function. They
express the UNC-30 homeodomain protein
(Jin et al., 1994
). UNC-30
co-regulates the expression of unc-25 and unc-47, along with
other unknown targets, to control multiple differentiation events in the type
D neurons (Eastman et al.,
1999
).
By contrast, the specification of the other seven GABA neurons depends on
both cell-specific and common factors. The LIM-6 transcription factor is
expressed in five GABA neurons, but has differential effects on their
differentiation. In lim-6 mutants, RMEL and RMER exhibit no
discernible abnormality, but AVL and DVB display variable defects in neurite
outgrowth and GABA expression, but not GABA vesicular packaging
(Hobert et al., 1999). AHR-1
acts as a cell-type-specific determinant to control the cellular
morphogenesis, but not neurotransmitter expression and packaging, of RMEL and
RMER. The function of AHR-1 depends on its ubiquitously expressed cofactor
AHA-1. lim-6 is probably a downstream target of ahr-1, but
lim-6 is unlikely to mediate all functions of ahr-1 in
RMEL/R neurons because neither glr-1 nor GABA expression is altered
in lim-6 mutants (Hobert et al.,
1999
) (this study).
Our observation that ectopic ahr-1 expression can transform RMED/V
to a RMEL/R-like fate further suggests that RMED/V cells may express some
cellular determinant(s) that represses ahr-1 expression and promotes
their fate specification. Although ceh-10 and lim-4 are
expressed in RMED and RMEV, respectively
(Forrester et al., 1998;
Hobert et al., 1999
), we find
that they do not function by repressing ahr-1 expression in RMED/V.
The analysis of double mutants among ahr-1, ceh-10 and lim-4
is also consistent with the conclusion that the specification of the four RME
neurons involves parallel signaling pathways that may use multiple
transcription cascades.
An ancestral role of AHR proteins is in regulating cell identity
All vertebrate AHRs bind dioxins through their PAS domains, and normally
reside in the cytoplasm in a complex with HSP90 and XAP2 chaperonins
(Petrulis and Perdew, 2002).
Dioxin binding induces nuclear translocation, allowing the formation of
AHR/ARNT heterodimer (Hahn,
2002
). Supporting the role of AHRs in toxin response,
AHR-deficient mice are resistant to many of the deleterious effects of
AHR-activating pollutants
(Fernandez-Salguero et al.,
1995
; Schmidt et al.,
1996
; Shimizu et al.,
2000
; Matikainen et al.,
2001
). However, these mice also show defects in liver, heart,
ovary, vascular and immune systems, and have reduced growth, reproduction and
survival, suggesting that AHR has important developmental functions, of which
little is understood. In zebrafish embryos, exposure to TCDD increases
apoptosis in the dorsal midbrain (Dong et
al., 2001
). In rat, AHR is expressed in the preoptic area of the
brain and co-localizes with GAD67, suggesting that the GABAergic neurons may
be the cellular targets of TCDD-induced AHR function
(Hays et al., 2002
).
The C. elegans AHR-1 and Drosophila AHR Spineless (SS)
have a PAS domain with divergent sequences and do not bind dioxin
(Powell-Coffman et al., 1998;
Butler et al., 2001
). In
Drosophila ss mutants, the distal antenna is transformed to distal
leg, and most of the tarsal region of each leg is deleted
(Duncan et al., 1998
). SS is
expressed in the tissues that are affected. Ectopic expression of ss
can induce ectopic antennal structures from some tissues, indicating that
ss functions as a tissue-specific factor to control distal antennal
identity. Thus, studies in Drosophila and those reported here reveal
an evolutionarily conserved function of AHRs as cell-type-specific
determinants in animal development.
How might AHR signaling have evolved? At least two AHR-1 partners have been
identified. One is ARNT, a ubiquitously expressed nuclear bHLH-PAS protein,
and the other is the cytoplasmic chaperonin HSP90
(Hahn, 2002). The ARNT
knockout mice died early, precluding the analysis of its involvement in AHR
developmental function (Kozak et al.,
1997
). The Drosophila ARNT Tango is required for
controlling antennal identity like ss
(Emmons et al., 1999
). We show
that C. elegans AHA-1 is required for AHR-1 in controlling RMEL/R
cell identity. Therefore, the AHR and ARNT are evolutionarily conserved
functional partners in regulating developmental processes.
Studies in yeast and mammalian cells have implicated two roles of HSP90 in
AHR function (Pongratz et al.,
1992). HSP90 sequesters AHRs in the cytoplasm in the absence of
ligands and also aids the proper folding of AHRs for ligand binding. The in
vivo functional involvement of HSP90 in AHR toxin response has not been
established. Although C. elegans AHR-1 can bind rabbit HSP90 in vitro
(Powell-Coffman et al., 1998
),
AHR-1 is normally localized to nucleus (H. Qin and J.A.P.-C., unpublished). We
find that daf-21/Hsp90 is not required for RMEL/R cell identity, nor
is it required for ectopic AHR-1 function, implying that AHR-1 can fold
properly in the absence of HSP90.
Drosophila SS and Tango are both normally localized to the
nucleus, and the nuclear localization of Tango depends on SS and other
bHLH-PAS factors (Ward et al.,
1998; Emmons et al.,
1999
). Similarly, the nuclear localization of C. elegans
AHA-1 in intestinal cells is dependent on the co-expression of a bHLH-PAS
dimerization partner HIF-1 (Jiang et al.,
2001
). The studies in invertebrates thus support a conclusion that
the subcellular localization of AHRs and ARNT is achieved through
co-expression of protein binding partners, not by ligand-induced nuclear
translocation (Crews and Fan,
1999
). Interestingly, expression studies in yeast show that the
domains of C. elegans AHR-1 predicted to bind HSP90 and ligand exert
a repressive function to inhibit nuclear translocation or transcriptional
activation of AHR-1 (Powell-Coffman et
al., 1998
). Thus, one may speculate that the toxin response of
AHRs in vertebrate animals evolved through a recently acquired interaction
with HSP90 or other chaperonins, which confers the toxin-inducible feature of
the mammalian AHRs.
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ACKNOWLEDGMENTS |
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Footnotes |
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* Present address: Department of Developmental Biology, Stanford University
School of Medicine, Stanford, CA 94305, USA
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