Department of Anatomy and Neurobiology, College of Medicine, University of California Irvine, Irvine, CA 92697-4040, USA
* Author for correspondence (e-mail: jsze{at}uci.edu)
Accepted 19 December 2003
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SUMMARY |
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Key words: C. elegans, Transcription, Serotonin biosynthesis, TRPV ion channels, Metabolic control
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Introduction |
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TRP-related proteins are a superfamily of cation channels that share
structural homology to the Drosophila transient receptor potential
(TRP) protein (reviewed by Clapham et al.,
2001; Montell et al.,
2002
). TRP channels act as molecular integrators of a wide range
of chemical and physical stimuli to regulate behavior and physiological
function in both vertebrates and invertebrates (reviewed by Scott and Zuker,
1998; Minke and Cook, 2002
).
Five genes in the C. elegans genome, ocr-1, ocr-2, ocr-3,
ocr-4 and osm-9, encode TRPV subfamily proteins characterized by
cytoplasmic N-terminal multiple ankyrin repeats, six transmembrane segments
and a non-conserved cytoplasmic C terminus
(Harteneck et al., 2000
;
Tobin et al., 2002
). These
TRPV genes are expressed in the sensory endings of chemosensory neurons and
have been shown to regulate sensory functions and social behavior
(Colbert et al., 1997
;
Tobin et al., 2002
;
de Bono et al., 2002
). In
mammals, TRPV channels transmit nociceptive stimuli such as pain
(Tominaga et al., 1998
) and
noxious heat (Caterina et al.,
1997
; Caterina et al.,
1999
). In addition, mammalian TRPV ion channels also mediate the
response to growth factors (Kanzaki et
al., 1999
). Agonists to TRPV channels induce hypothermia
(Meller et al., 1992
;
Szallasi and Blumberg, 1996
)
and modulate oxygen consumption (Colquhoun
et al., 1995
). Mammalian TRPV proteins are expressed in the
sensory neurons, as well as in the CNS
(Tominaga et al., 1998
;
Hayes et al., 2000
;
Mezey et al., 2000
;
Delany et al., 2001
). It has
been postulated that TRPV ion channels regulate the release of neural
mediators to modulate endocrine activity
(Szallasi and Blumberg, 1996
),
but in vivo evidence has not yet been reported.
We describe the effect of mutations in two TRPV ion channel genes,
osm-9 and ocr-2, on biosynthesis of 5HT in C.
elegans. Previously, we demonstrated that the tph-1 gene, which
encodes the key 5HT biosynthesis enzyme tryptophan hydroxylase, is essential
for 5HT biosynthesis and that tph-1 expression is regulated by
cell-specific mechanisms (Sze et al.,
2000; Sze et al.,
2002
). In this study we show that a signaling pathway involving
the osm-9 and ocr-2 TRPV channel proteins, CaMKII
specifically regulates tph-1 expression in the serotonergic
chemosensory neurons ADF. Results from this study reveal a remarkably
neuron-specific mechanism regulating 5HT biosynthesis and provide genetic
insights into how a neuron transduces the events at the cell-surface to 5HT
signaling.
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Materials and methods |
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Isolation and characterization of osm-9(yz6) and ocr-2(yz5) mutants
The yz6 and yz5 mutations were isolated based on
reduction/absence of GFP in the ADF neurons after ethylmethane sulfonate
mutagenesis of wild-type animals carrying an integrated tph-1::gfp
transgene. The mutagenesis and mutant screens have been described previously
(Sze et al., 2002). We
screened about 6500 haploid genomes and isolated 24 mutants. None of the
mutations completely eliminates tph-1::gfp expression in the ADF
neurons, but yz12 (Sze et al.,
2002
), yz5, yz6 and other three mutants showed stronger
effects. Genetic mapping and complementation analysis indicated all these six
strong mutants as single alleles, thus the screen is probably unsaturated. We
mapped yz6 between the polymorphisms in the clones C09G12 and M02B7,
and yz5 between C49H3 and C01F6. A PCR fragment of the cosmid M57
containing 2.8 kb of the upstream sequence, exons/introns and 1.3 kb
downstream sequence of osm-9 restores tph-1::gfp expression
in ADF of yz6 animals. A PCR fragment of the cosmid T09A12 containing
2.5 kb upstream sequence, exons/introns and 1.8 kb downstream sequence of
ocr-2 restores tph-1::gfp expression in yz5
mutants. The molecular lesion of the mutations was determined by PCR
amplification of the exons and exon/intron boundaries from the mutant strains
and sequencing the PCR fragments.
Expression of osm-9 from heterologous promoters
The osm-9 and ocr-2 genes are co-expressed in six pairs
of neurons: ADF, AWA, ADL, ASH, PHA and PHB
(Colbert et al., 1997;
Tobin et al., 2002
). Chimeric
constructs were generated by expressing wild-type osm-9- or
ocr-2-coding regions under the control of heterologous promoters that
are expressed in a subset of these six pairs of the neurons. The expression
pattern of the heterologous promoters overlaps with osm-9 and
ocr-2 in the following neurons: odr-7, AWA
(Sengupta et al., 1994
);
osm-10, ASH, PHA and PHB (Hart et
al., 1999
); tax-2, PHA and PHB
(Coburn and Bargmann, 1996
);
cat-1, ADF (Sze et al.,
2002
); lin-11, ADF, ADL
(Hobert et al., 1998
);
tph-1(BC), ADF (this work). In each case, we first constructed a
fusion of the promoter region to the GFP and unc-54 3'-uncoding
sequences in the plasmid pPD97.75 (A. Fire) to confirm the expression pattern,
then, we replaced the GFP sequence with a genomic sequence encompassing the
entire intron and exon regions of osm-9 or ocr-2. Individual
constructs were introduced into yz6 or yz5 mutants carrying
the integrated tph-1::gfp reporter. The tph-1(BC) construct
was generated by inserting the sequence from 132 to 377 upstream
of the tph-1 translational start [the BC region as described
previously (Sze et al., 2002
)]
to a minimal promoter of the pes-10 gene in the GFP vector pPD122.53
(A. Fire). The plasmid pRF4 containing the dominant Rol-6 gene was co-injected
as a transgenic marker for Promoter::gfp constructs, and a plasmid containing
elt-2::gfp (a gift from J. McGhee) as the marker for
Promoter::osm-9 and Promoter::ocr-2 constructs.
GFP expression and Immunoanalysis
The expression pattern of these GFP transgenes in wild-type animals has
been published: the tph-1::gfp, lin-11::gfp and cat-1::gfp
transgenes were integrated into the chromosomes, and gtpch-1::gfp was
carried as extra chromosomal arrays
(Hobert et al., 1998;
Sze et al., 2000
;
Sze et al., 2002
). The
individual transgenes were crossed into mutants. Thus, the expression of the
same transgene in wild-type and mutant animals was compared.
To quantify GFP intensity of tph-1::gfp in the ADF neurons, the images were captured with a Zeiss AxioCam digital camera at a fixed exposure time, and the fluorescence within a 25x25 pixel area of the cell body was scored, hence the same dimension of the ADF neurons in different genetic background was compared.
The staining of anti-5HT antibody was performed using the McIntire-Horvitz
whole-mount procedure with modifications as described
(McIntire et al., 1992;
Sze et al., 2000
).
Behavioral assays
Feeding and egg-laying assays were conducted with young adult animals.
Well-fed larval stage 4 animals (L4) were picked onto fresh plates seeded with
bacteria as the food, and allowed to develop 20 hours at 20°C.
Feeding behavior was assayed by measuring the rate of pharyngeal pumping,
which was scored by counting pharynx terminal bulb contractions
(Duerr et al., 1999
;
Sze et al., 2000
). Egg-laying
behavior was scored by counting the number of fertilized eggs accumulated
inside of the uterus of adults, using DIC optics
(Sze et al., 2000
).
For Dauer assays, 10 young adult animals of a strain were transferred onto
a fresh plate and allowed to lay eggs for overnight. The parents were then
removed, progeny were allowed to develop at 15°C, and the number of Dauers
and L4/adults was scored 5-6 days later. Notice a higher Dauer frequency of
tph-1;daf-7 double mutant animals than we previously reported
(Sze et al., 2000). This
difference is due to different time points at which we scored Dauers.
tph-1;daf-7 mutants grow slower, some of the animals were still at
pre-Dauer stages at the earlier time point.
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Results |
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yz5 and yz6 are two of the nss mutations that specifically downregulate tph-1 expression in the ADF neurons. In wild-type animals, tph-1::gfp is highly expressed in the ADF, NSM and HSN neurons, but the GFP level in the ADF neurons is dramatically reduced or undetectable in yz5 and yz6 mutants (Fig. 1B, Table 1). Consistent with the essential role of tph-1 in 5HT biosynthesis, staining of the mutant animals with anti-5HT antibody shows reduced/absence of 5HT immunoreactivity in the ADF neurons (Fig. 1C). However, neither the mutation nor yz5;yz6 double mutation has a detectable effect on tph-1::gfp expression or 5HT immunoreactivity in other serotonergic neurons (Table 1; Fig. 1B,C). The ADF neurons are the only serotonergic sensory neurons in hermaphroditic C. elegans, the data suggest that yz5 and yz6 specifically regulate the serotonergic phenotype of sensory neurons.
|
TRPV ion channels act cell autonomously to control 5HT biosynthesis
Both osm-9 and ocr-2 are expressed in the ADF neurons
(Colbert et al., 1997;
Tobin et al., 2002
), but not
in other serotonergic neurons (Fig.
2A). Beside ADF, osm-9 and ocr-2 also are
co-expressed in five pairs of non-serotonergic chemosensory neurons: the AWA,
ADL, ASH neurons in the head, and the PHA and PHB neurons in the tail
(Tobin et al., 2002
). These
head neurons, as well as ADF, are component neurons of the amphid sensory
organ, and each class senses distinct signals
(Bargmann and Horvitz, 1991a
).
The cell bodies of these head neurons are clustered together, and their
processes run parallel and are interconnected directly or indirectly en
passant (White et al., 1986
)
(Fig. 1A). The TRPV channels
could act in the ADF neurons to control tph-1 expression, or they
could function in the other chemosensory neurons that regulate ADF neural
activity. The AWA neurons detect the attractive odorant diacetyl, and the ASH
and ADL neurons sense aversive signals; ocr-2(ak47) and
osm-9 mutant animals are defective in sensing these sensory signals
(Colbert et al., 1997
;
Tobin et al., 2002
). We tested
whether disruption of these sensory signaling is a cause of reducing
tph-1::gfp expression. No GFP reduction was observed in animals with
defective diacetyl receptor (odr-10)
(Sengupta et al., 1996
) or
with defective ASH, ADL (osm-11) function
(Table 1). Thus,
osm-9/ocr-2 function in these sensory signaling is not required to
activate tph-1 expression in the ADF neurons.
|
|
Does this TRPV channel signaling specifically regulate tph-1
expression, or does it regulate the expression of all genes involved in 5HT
synthesis and neurotransmission? We have explored this question by examining
GFP reporters of marker genes. In each case, the GFP reporter construct was
first introduced into wild-type animals, and the resulting transgene was then
crossed into mutants. Thus, the expression of the same transgene in different
genetic backgrounds was compared. CAT-1/vesicular monoamine transporter is
required for 5HT neurotransmission (Duerr
et al., 1999; Nurish et al., 1999). cat-1::gfp is a
functional fusion of GFP to the entire protein coding segment of the
cat-1 gene and is localized to the synapses of the serotonergic
neurons (Sze et al., 2002
).
The gene F32G8.6 encodes a probable GTP-cyclohydrolase I (gtpch-1), a
co-factor of tryptophan hydroxylase for 5HT biosynthesis, and a
gtpch-1::gfp fusion gene also is expressed in the serotonergic
neurons (Sze et al., 2002
).
Unlike the dramatic reduction of tph-1::gfp in the ADF neurons, there
is no significant reduction of cat-1::gfp or gtpch-1::gfp in
yz6 and yz5 mutant backgrounds
(Fig. 2C,D). These observations
are consistent with our previous results that the expression of tph-1,
cat-1 and gtpch-1 is differentially regulated in serotonergic
neurons (Sze et al., 2002
).
These data demonstrate a great specificity of the TRPV channel signaling
within the ADF neurons and suggest the transcriptional regulation of the
tph-1 gene as a major target.
The TRPV channel signaling modulates a neuron-specific transcription program
Analysis of the tph-1 promoter has revealed a discrete
cis-regulatory region essential for tph-1 expression in the ADF
neurons (Sze et al., 2002). We
investigated whether the TRPV ion channel signaling acts through this
neuron-specific transcriptional regulatory mechanism. A GFP reporter under the
control of the sequence 132 bp to 377 bp of tph-1 and a
minimal promoter from the pes-10 gene is specifically expressed in
the ADF neurons of wild-type animals, but the ADF GFP intensity is
significantly reduced in yz6 mutant background
(Fig. 3A). Thus, the 246 bp
cis-regulatory region is sufficient to activate tph-1 expression in
the ADF neurons, and signaling from the OSM-9 and OCR-2 ion channels regulates
the activity of this neuron-specific transcriptional regulatory program.
|
unc-43 CaMKII acts downstream or in parallel with the TRPV ion channels to modulate 5HT biosynthesis
The odr-3 G protein is essential for osm-9 and
ocr-2 function in olfactory, osmosensory and mechanosensory behaviors
mediated by the AWA and ASH neurons
(Roayaie et al., 1998
;
Colbert et al., 1997
;
Tobin et al., 2002
). It has
been proposed that ODR-3 activity modulates the outputs of the TRPV channel
signaling (Roayaie et al.,
1998
). odr-3 also is expressed in the ADF neurons;
however, the odr-3(n2150) deletion mutation does not cause a
significant reduction of tph-1::gfp expression
(Fig. 3B). Thus, OSM-9 and
OCR-2 can activate tph-1 expression in the absence of odr-3
activity. Beside odr-3, the ADF neurons express two other G
proteins, gpa-3 and gpa-13
(Jansen et al., 1999
).
tph-1::gfp expression is unaffected in gpa-3 or
gpa-13 deletion mutants (Fig.
3B). However, animals bearing a double mutation of TRPV and
G
still exhibit reduced tph-1::gfp expression in the ADF
neurons similar to the TRPV mutants. These data indicate that unlike the role
of ODR-3 in the sensory behaviors, the G
proteins do not play an
essential role in OSM-9/OCR-2-dependent regulation of tph-1
expression. Because the sensory behaviors and 5HT production are mediated by
different neurons, our results suggest that OSM-9 and OCR-2 TRPV channels in
different neurons may be regulated by different mechanisms.
CaMKII is a critical mediator of Ca2+ signaling. The
unc-43 gene encodes the only C. elegans CaMKII
(Reiner et al., 1999;
Rongo and Kaplan, 1999
). An
unc-43 loss-of-function mutation causes a twofold reduction of
tph-1::gfp expression in the ADF neurons
(Fig. 3B), but has no effect on
other serotonergic neurons (not shown). Conversely, the unc-43(n498)
gain-of-function mutation partially blocks the downregulation of
tph-1 expression in yz6
(Fig. 3b) and yz5
mutants (data not shown). One simple model to explain these data would be that
activation of OSM-9 and OCR-2 channels increases ADF intracellular
Ca2+ which stimulates UNC-43 to induce tph-1
transcription, whereas the unc43(n498) mutation, which causes
constitutive Ca2+-independent activity
(Reiner et al., 1999
),
bypasses the need of the channel function. However, these results do not
exclude the possibility that UNC-43 acts less directly in the TRPV channel
signaling pathway. These results suggest that CaMKII acts downstream of or in
parallel with the OSM-9 and OCR-2 TRPV channels to control 5HT production in
the ADF chemosensory neurons.
Dauer phenotype of osm-9 and ocr-2 mutants
We find that both osm-9 and ocr-2 mutants show
developmental defects reminiscent of tph-1 deletion mutants
(Fig. 4A). The DAF-2/insulin
receptor and DAF-7/TGFß signaling act in parallel to control whether an
animal enters the reproductive lifecycle or developmentally arrests at the
metabolically inactive Dauer larval stage. Disruption of either pathway causes
conditional abnormal arrest at the Dauer stage, but disruption of both the
pathways causes constitutive Dauer arrest
(Ogg et al., 1997) (reviewed
by Riddle, 1997
). Similar to
the tph-1 deletion mutation, the osm-9(yz6);
osm-9(ky10) and ocr-2(yz5) mutations enhance the Dauer
phenotype of daf-7(e1372) mutants
(Fig. 4A). At the 15°C
growth temperature, about 10% of daf-7 mutant animals arrest as
Dauers, but more than 70% form Dauers when daf-7 mutants carry a
mutation in osm-9 or ocr-2. Ninety-eight percent of
daf-7;tph-1 double mutant animals form Dauers, whereas 10-15%
tph-1 mutants form Dauers (Sze et
al., 2000
). None of the TRPV mutants on their own formed Dauers
when assayed under the same condition, although they grow slower than
wild-type animals. Because e1372 is a daf-7-null mutation,
this enhanced Dauer phenotype of the double mutants implies that the
TRPV-mutations affect a pathway parallel to daf-7.
|
osm-9 and ocr-2 mutant animals do not display every
deficit observed in mutants with all the serotonergic neurons defective. 5HT
regulates several C. elegans behaviors. For example, applying
exogenous 5HT to C. elegans stimulates pharyngeal pumping and
egg-laying (Avery and Horvitz,
1990; Weinshenker et al.,
1995
), whereas 5HT-deficient mutants tph-1 and
cat-1 exhibit a slower pumping rate and accumulate a large number of
fertilized eggs in the uterus (Duerr et
al., 1999
; Sze et al.,
2000
). However, osm-9 and ocr-2 mutant animals
do not accumulate excess eggs in the uterus and their pharyngeal pumping rates
are equivalent to wild-type animals (Fig.
4B,C). Thus, 5HT signals from the other neurons are sufficient for
these behaviors. But, we cannot exclude subtle behavioral changes that are
difficult to detect visually.
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Discussion |
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A TRPV channel-dependent transcription program controls 5HT signaling
It has been demonstrated in many experimental systems that sensory stimuli
induce 5HT signals to produce changes in behavior and physiology (e.g.
Barzilai et al., 1989;
Boadle-Biber, 1993
;
Milner et al., 1998
). Until
this study, no endogenous membrane protein has been shown to act in a
serotonergic neuron to regulate 5HT signaling. One important finding from this
study is the pronounced effect of osm-9 and ocr-2 mutations
on the expression of the 5HT synthesis gene tph-1
(Fig. 1). This indicates that
the production of 5HT is a site where sensory information is integrated to 5HT
signaling. 5HT can be released by controlled exocytosis at the synapses as
well as via paracrine `volume transmission', and even during the controlled
exocytosis it is newly synthesized 5HT preferentially released to induce
changes in the postsynaptic targets
(Attwell et al., 1993
;
Sanders-Bush, 1982
). Hence,
the level of 5HT production is one mechanism controlling both forms of 5HT
neurotransmission.
Transcriptional regulation may represent a general principle of regulation
of hormones and neuromodulators. For example, C. elegans' favorite
growth environment upregulates the expression of the daf-7/TGFß
and daf-28/insulin genes to induce C. elegans proceeding
reproductive development (Schackwitz et
al., 1998; Li et al.,
2003
); in rats, noxious sound stimuli may alter the transcription
of their tryptophan hydroxylase gene in a neuron-specific manner (reviewed by
Boadle-Biber, 1993
); and the
expression of tyrosine hydroxylase can be modulated by hormones in mice
(Kumer and Vrana, 1996
).
Transcriptional regulation of these signaling molecules is likely a mechanism
to exert a relatively slow but profound effect in the signaling pathways.
Mechanisms of TRPV channel action in the ADF neurons
Our genetic results indicate that the osm-9 and ocr-2
channel proteins interact with different signaling transduction pathways to
induce different behavioral outputs. osm-9 and ocr-2 are
co-expressed in four pairs of the amphid sensory neurons, and are required for
a normal response to attractive and aversive odorants mediated respectively by
AWA, and ASH and ADL, as well as for ASH-mediated mechanosensory and
osmosensory function (Colbert et al.,
1997). There are genetic evidences indicating that osm-9
and ocr-2 function in these sensory behaviors requires the
odr-3 G
protein (Roayaie
et al., 1998
). However, tph-1 expression is unaffected by
mutations in odr-3 or in other two G
protein expressed in the
ADF neurons (Fig. 3B). Although
the exact mode of activation of OSM-9 and OCR-2 in any neuron has not yet been
defined, our data indicate that the activity of the channels in the ADF
neurons is regulated by different signaling molecules. It is interesting to
note that osm-9 and ocr-2 also act in the ASH and ADL
neurons to regulate social behavior independent of odr-3 activity (de
Mono et al., 2002); hence, the OSM-9 and OCR-2 can induce specific behaviors
by coupling distinct signaling systems.
The reciprocal effects of the unc-43 CaMKII loss- and
gain-of-function mutations on tph-1 expression indicate that the
amount of Ca2+ modulates 5HT biosynthesis
(Fig. 3B). The TRP superfamily
is Ca2+-permeable channels, and CaMKII is known as an important
mediator of Ca2+ signaling (reviewed by
Hanson and Schulman, 1992).
Our genetic study shows that the constitutively active,
Ca2+-independent unc-43(n498) CaMKII
(Reiner et al., 1999
) can
partially activate tph-1 expression in osm-9 deletion mutant
animals (Fig. 3B). These
results support the model that UNC-43 is a downstream effector of the OSM-9
and OCR-2 channels: Ca2+ influx through OSM-9 and OCR-2 activates
UNC-43 CaMKII, which induces phosphorylation cascades to activate
tph-1 expression. However, unc-43(lf) mutants still express
a substantial amount of tph-1, and the unc-43(gf) mutation
does not completely bypass OSM-9 activity, indicating that other OSM-9/OCR-2
downstream signaling molecules may act in parallel with UNC-43 to regulate
tph-1 expression.
The effect of OSM-9 and OCR-2 TRPV ion channels in the ADF neurons is
strikingly specific, given the involvement of Ca2+ and CaMKII. The
general architecture of the ADF neurons is unaffected, we could not detect a
significant change in the expression levels of ADF marker genes or genes
directly involved in the serotonergic phenotype, nor we could detect an effect
of unc-43(lf) or (gf) mutations on tph-1 expression in other
serotonergic neurons. This specificity demonstrates that `multi-functional,
widespread' signaling molecules may play a refined role in a particular native
cellular setting. It is conceivable that such differential regulation of the
serotonergic phenotype genes would allow the ADF neurons to adjust 5HT
neurotransmission in response to multiple sensory signals. As TRPV channels
are expressed in the serotonergic locus in mammals
(Tominaga et al., 1998;
Mezey et al., 2000
), it would
be interesting to determine whether there is a link between TRPV mutations and
5HT deficiency in human.
The role of TRPV channels in a sensory-neuroendocrine signaling pathway
The Dauer phenotype of the osm-9 and ocr-2 mutants
demonstrates a genetic link between the TRPV ion channels and endocrine
signaling (Fig. 4). C.
elegans Dauer/non-Dauer development reflects two alternative metabolic
states controlled by sensory inputs to neuroendocrine signaling pathways. The
pathways from DAF-7/TGFß and DAF-2/insulin receptor converge to stimulate
reproductive growth; harsh environmental conditions transduced by the amphid
chemosensory neurons suppress the endocrine signaling to induce Dauer arrest
(reviewed by Riddle, 1997).
Our enhancement and suppression genetics implies that osm-9 and
ocr-2 regulate the DAF-2/insulin-receptor signaling pathway
(Fig. 4). The TRPV channels are
probably acting in the ADF neurons to modulate endocrine activity: worms
bearing defective ADF neurons tend to form Dauers
(Shakir et al., 1993
), and
laser ablation experiments implicate ADF but not the other osm-9 and
ocr-2 co-expressing chemosensory neurons in Dauer formation
(Bargmann and Horvitz, 1991b
).
However, expression of the wild-type osm-9-coding sequence under a
lin-11 promoter only partially suppresses daf-7;osm-9 Dauer
phenotype, indicating that osm-9 activity in other cells also
modulates Dauer phenotype. Alternatively, the lin-11 promoter may not
be able to express sufficient amount of osm-9 to induce a wild-type
level of ADF 5HT signals (Table
2), or ectopic expression of osm-9 in other
lin-11-expressing cells may interfere with the neuroendocrine
signaling cascades for normal development. In mammals, 5HT regulates insulin
synthesis, release and response (Breum et
al., 1995
; Peschke et al.,
1997
). It has been proposed that a feedback regulatory loop
between hypothalamus 5HT and circulating hormones such as insulin, leptin and
adipose tissue-derived hormone modulates the satiety and maintains metabolic
and energy homeostasis (Leibowitz and
Alexander, 1998
). Interestingly, mouse TRPV-like channels can be
activated by insulin-like growth factors
(Kanzaki et al., 1999
). We
propose that 5HT is one mediator of TRPV channels and endocrine activity.
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ACKNOWLEDGMENTS |
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