Chemical Senses Vol. 29 No. 9 © Oxford
University Press 2004; all rights reserved
Sex-specific Responses to Urinary Chemicals by the Mouse Vomeronasal Organ
1 Alabama State University, Department of Biological Sciences, Montgomery, AL 36101-0271, USA 2 Current address: Department of Biological Science Program in Neuroscience and Molecular Biophysics, The Florida State University, Tallahassee, FL 32306, USA
Correspondence to be sent to: Kennedy Wekesa, Department of Biological Sciences, Alabama State University, Montgomery, AL 36101-0271. e-mail: kwekesa{at}asunet.alasu.edu
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Social behaviors of most mammals are affected by chemical signals, pheromones, exchanged between conspecifics. Previous experiments have shown that behavioral responses to the same pheromone differ depending on the sex and endocrine status of the respondent. Although the exact mechanism of this dimorphism is not known, one possible contributor may be due to sexually dimorphic receptors or due to differences in central processing within the brain. In order to investigate the differences in response between male and female mice to the same pheromonal stimulus two urinary compounds (2-heptanone and 2,5-dimethylpyrazine) were used to stimulate the production of Inositol (1,4,5)-trisphosphate (IP3) in microvillar membrane preparations of the vomeronasal organ as an indirect measurement of pheromonal stimulation. Incubation of such membranes from prepubertal mice with urine from the same sex or opposite sex, results in an increase in production of IP3. This stimulation is mimicked by GTP
S and blocked by GDPßS. Furthermore we
found that 2-heptanone present in both male and female urine was capable of
stimulating increased production of IP3 in the female VNO but not
the male VNO. Finally, 2,5-dimethylpyrazine present only in female urine was
also only capable of stimulating increased production of IP3 in the
female VNO.
Key words: IP3, mice, pheromones, signal transduction, urinary compounds, VNO
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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The mammalian olfactory system recognizes a wide range of molecules that represent important information about an animal’s environment. The main olfactory system is used to locate food and detect predators or prey, whereas a second system, called the vomeronasal system or accessory olfactory system recognizes species-specific chemical signals (pheromones) which are used to coordinate social and reproductive behaviors. The accessory olfactory system consists of the vomeronasal organ (VNO), the vomeronasal glands and the accessory olfactory bulb (AOB). The VNO is distinctly separated from the nasal cavity in most amphibia, reptiles and nonprimate mammals, but is absent in birds and adult catarrhine monkeys and apes (Stoddard, 1980
). The VNO has the appearance of a
paired, tubular structure divided by the nasal septum, each side having a
crescent-shaped lumen lined with receptor neurons on the medial concave side
and filled with fluid from the vomeronasal glands (D¿ving and Trotier, 1998). Lateral to the
lumen are large blood vessels and sinuses that are innervated by the autonomic
nervous system inducing vasodilations and vasoconstrictions that produce a
pump-like action for stimulus access to the lumen (Meredith, 1994).
The vomeronasal neurons can be divided into two main groups: (1) the
most apical zone of the neuroepithelium contains vomeronasal neurons that
project to the anterior aspect of the accessory olfactory bulb and express the
G-protein G
i2 and members of either V1R or V3R families of
putative pheromone receptors; and (2) the basal zone contains vomeronasal
neurons that project to the posterior aspect of the accessory olfactory bulb
and express the G-protein G0 and members of the V2R family of
receptors (Halpern et al.,
1995;
Berghard and Buck,
1996;
Jia and Halpern,
1996;
Wekesa and Anholt,
1999;
Dulac, 2000;
Pantages and Dulac,
2000). V1R receptors are the same general type G-protein-coupled
receptor as the olfactory receptor and there are estimated to be 
150
different types of receptors (Herrada
and Dulac, 1997;
Matsunami and Buck,
1997;
Ryba and Tirindelli,
1997;
Rodriguez et al.,
2002). V2Rs on the other hand are similar to metabotropic glutamate
receptors in that they have a long extracellular N-terminal region believed to
be involved in ligand binding. There are estimated to be 100 V2Rs in rodents,
arrayed into several sub-families (Herrada and Dulac, 1997;
Matsunami and Buck,
1997;
Ryba and Tirindelli,
1997). Vomeronasal transduction in vertebrates is distinct and
driven by phospholipase C (PLC)-induced production of IP3 and the
subsequent increase in intracellular calcium concentration (Luo et al., 1994;
Inamura et al.,
1997;
Wekesa and Anholt,
1997;
Holy et al.,
2000;
Inamura and Kashiwayanagi,
2000;
Leinders-Zufall et
al., 2000;
Cinelli et al.,
2002;
Wekesa et al.,
2003). Although there is some consensus on the role of PLC in the
transduction process, there is still debate on the type of G-protein involved
and the role of IP3 (Lucas
et al., 2003). Studies in mice using bacterial toxins such
as pertussis that lead to ADP-ribosylation of G-protein alpha subunits of
G0 and Gi2 have been unable to block the production of
IP3 in the VNO, thus suggesting a role for Gq/11 in signal
transduction (Wekesa et al.,
2003)
Previous experiments have shown that behavioral responses to the same
pheromone differ depending on the sex and endocrine status of the respondent.
For example, in male mice, exposure to female pheromones facilitates
luteinizing hormone secretion (Johnston
and Bronson, 1982;
Coquelin et al.,
1984) and stimulates ultrasonic vocalizations (Nyby et al., 1979), whereas
exposure to male pheromones elicits inter-male aggressive behavior (Guillot and Chapouthier, 1996). In
contrast, exposure of females to female pheromones delays puberty and
suppresses estrus (Van der Lee and
Boot, 1959), while male pheromones accelerate puberty (Vandenbergh, 1969;
Lombardi and Vandenbergh,
1977), cause estrous cycle synchronization (Whitten, 1959) and induce pregnancy block to
recent mating (Bruce, 1959).
In rodents, the major source of pheromones seems to be the urine; however very
few volatile (Novotny et al.,
1985) and non-volatile (Vandenbergh et al., 1975) urinary
substances producing a definite endocrine or behavioral response have been
identified. The best-characterized non-volatile urinary components in male
mouse urine are the ‘major urinary proteins’ (Clissold et al., 1984). It has been
suggested that the major urinary proteins are involved in puberty acceleration
(Vandenbergh et al.,
1975;
Clark et al.,
1985;
Mucignat-Caretta et
al., 1995), estrus synchronization and puberty delay
(Jemiolo et al.,
1989;
Novotny et al.,
1999). The major urinary proteins of mice belong to the super
family of lipocalins, a structurally homologous but diverse family of
extracellular proteins, characterized by their ability to bind small,
principally hydrophobic molecules (Flower, 1996). Urine also contains smaller
molecules that have been shown to have pheromonal effects. Two such molecules
are 2,5-dimethylpyrazine and 2-heptanone which reportedly are believed to have
diverse chemosignaling functions. 2-Heptanone found in both male and female
urine has been shown to extend the estrous cycle in female mice whereas
2,5-dimethylpyrazine, found only in female urine, acts to delay puberty in
females (Novotny et al.,
1985;
Jemiolo et al.,
1989;
Novotny, 2003).
Using a procedure that we have developed for the preparation of a VNO membrane fraction enriched in dendritic microvillar membranes, we report that two urinary compounds, 2-heptanone and 2,5-dimethylpyrazine, stimulate the production of IP3 when applied to microvillar VNO membranes from pre-pubertal females but not from pre-pubertal males.
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Animals
CD-1 mice Mus musculus were initially purchased from Charles River Laboratories (Wilmington, MA). They were maintained in a breeding colony in the Department of Biological Sciences at Alabama State University, Montgomery, AL. Animals were housed in facilities inspected and approved by the Institutional Animal Care and Use Committee and cared for according to the NIH Guidelines for care and use of laboratory animals. Mice were kept in single sex pairs in Nalgene cages 26 x 21 x 14 cm, at 24–28°C room temperature and a 12/12 h light/dark cycle. Food and water were given ad libitum. Mice used for VNO membrane preparations were prepubertal (20–21 days old) whereas mice used for urine collection were adults (60–90 days old).
Membrane preparation
VNOs were dissected from their crevices in the nasal cavity, removed
from the cartilaginous capsule and frozen on dry ice. The tissues were minced
with a razor blade then crushed with a Teflon pestle and subjected to
sonication for 2–5 min in ice-cold phosphate-buffered saline (PBS) in a
Bransonic bath sonicator. The resulting suspension was layered on a 45%
(w/w) sucrose cushion and centrifuged at 4°C for 30 min at 30 000
r.p.m. in a Beckman SW55Ti rotor. The membrane fraction was collected and
centrifuged as before for 15 min to pellet the membranes. The membranes were
resuspended in 100 µl of ice-cold PBS. Protein concentration was then
determined according to the method of
Lowry et al.
(1951).
The procedure used for the preparation of microvillar membranes is
modeled after well-established methods for harvesting olfactory cilia from
olfactory neuroepithelium (Anholt et
al., 1986;
Anholt, 1995). The
sonication of membranes results not only in the detachment of olfactory
microvilli, but also in the detachment of microvilli from sustentacular cells
and plasma membrane fragments from other components of the neuroepithelium.
Electron microscopic examination of these preparations revealed vesicles,
axonemal structures devoid of a plasma membrane and axonemal structures
associated with membrane fragments (Anholt et al., 1986;
Anholt, 1995). The
membrane preparation we refer to as ‘microvillar membranes’ is,
therefore, likely to contain contaminants derived from other components of the
VNO, including microvillar membranes from supporting cells and it is difficult
to estimate the purity of the preparation precisely. However, our preparation
appears to be sufficiently enriched in chemosensory membranes for the purpose
of our studies.
Second messenger assay
Adult gender-specific urine was collected over a 5 day period,
pooled, spun for 5 min at 5000 g, decanted and frozen as aliquots at
–80°C until assayed. Female urine was collected from adult sexually
active females at the end of their estrous cycle, whereas male urine was
collected from sexually active adult males. IP3 kits were purchased
from Perkin Elmer Life Sciences Inc. (Boston, MA). For IP3 assays,
reactions were incubated for 1 min at 37°C in 25 mM Tris-acetate buffer pH
7.2, 5 mM Mg-acetate, 1 mM DTT, 0.5 mM ATP, 0.1 mM CaCl2, 10
µM GTP and 20 µg VNO membrane protein. Reactions were terminated by
the addition of 1 M trichloroacetic acid. The chemicals, 2-heptanone and
2,5-dimethylpyrazine were purchased from Aldrich Chemical Co. (Milwaukee, WI).
The non-hydrolysable forms of G-protein guanosine
5'-O-(3-thiotriphosphate) (GTPS) and guanosine
5'-O-(2-thiodiphosphate) (GDPßS) were purchased from
Boehringer Mannheim (Indianapolis, IN). Differences between experimental and
control animals were analyzed by analysis of variance (ANOVA).
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GTP-dependent increases in IP3 levels induced by male and female urine in VNO membranes from female mice
To study transduction pathways activated by pheromonal stimuli, we
developed preparations enriched in microvillar membranes from VNOs of
prepubertal females. Incubation of microvillar VNO membranes from prepubertal
females with adult male and female urine results in a significant increase in
the production of IP3 (P < 0.05; Figure
1). We were
further able to show that the response that we measured was G-protein dependent
by blocking the response with GDPßS and stimulating with GTPS.
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Increase in IP3 levels induced by 2-heptanone and 2,5-dimethylpyrazine in VNO membranes from prepubertal female mice
Incubation of microvillar membranes from VNOs of prepubertal female
mice with 2-heptanone and 2,5-dimethylpyrazine resulted in a robust increase of
IP3 as compared to the control (P < 0.05; Figure
2). This effect
was blocked by incubation with GDPßS. Although the response was
significantly higher than control, it was not as high as stimulation with male
or female urine. These results complement behavioral studies that have shown
that these compounds have possible chemosignaling function in female mice. It
has been shown that 2-heptanone extends estrus in female mice (Jemiolo et al., 1989),
whereas 2,5-dimethylpyrazine delays puberty in female mice (Novotny et al., 1985).
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GTP-dependent increases in IP3 levels induced by male and female urine in VNO membranes from prepubertal male mice
Incubation of microvillar VNO membranes from prepubertal males with
adult male or female urine results in a significant increase in the production
of IP3 (P < 0.05; Figure
3). This response
is mimicked by GTPS and blocked by GDPßS.
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Incubation of microvillar membranes from prepubertal male VNO with 2-heptanone and 2,5-dimethylpyrazine does not result in an increase in IP3 levels. Stimulation of prepubertal male VNO membranes by 2,5-dimethylpyrazine and 2-heptanone did not produce a significant increase in IP3 (Figure 4). These results suggest that these two urinary chemicals are specific for female chemosignals and not male. It is possible that these two compounds may mediate their effects through another second messenger such as cAMP. This is highly unlikely since most of the current data indicates that IP3 is the dominant second messenger within the vomeronasal system.
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There are several studies that have shown sexual dimorphism in the vertebrate vomeronasal organ in terms of size of the VNO or number of neurons in the VNO. There is evidence that more neurons are present in the VNO of males than female rats (Segovia and Guillamon, 1982
).
Zufall et al.
(2002) tested the effects of 2-heptanone and 2,5-dimethylpyrazine
on female mice vomeronasal neurons as measured by an electrovomeronasogram
(EVG). They found that mouse vomeronasal neurons are extremely sensitive and
highly selective in their response to specialized pheromonal cues and appear to
recognize only one or very few pheromonal components (Zufall et al., 2002).
Holy et al.
(2000) using a multielectrode array to record from sheets of VNO
neuroepithelium found that there are neurons in male and female VNOs that
respond uniquely to pheromones of one sex. There is further evidence that
neurons within defined subdivisions of the VNO respond differentially to
pheromones and moreover the responses differ in the VNO of females and males
(Halem et al.,
2001).
Most of the previous biochemical experiments have focused on
interactions between males and females thus ignoring chemical communication
between members of the same sex. It is well known that female mice send
chemical signals to other females that may lead to estrus suppression, puberty
delay, or estrus synchronization (Keverne, 1983;
Vandenbergh, 1994).
Males on the other hand send signals to other males during the formation of
hierarchies in social systems (Keverne,
1983;
Vandenbergh, 1994).
Also most of the previous experiments have focused mainly on female response to
male chemical cues. Here we show that males can respond to female cues with an
increase in IP3, thus suggesting that pheromonal cues from females
to males that lead to male specific behaviors such as increase in ultrasonic
vocalization or reduction in aggression may be mediated by IP3. The
signal transduction pathway of such communication between members of the same
sex has also not been explored up to now. Our data indicates that pheromones in
male mice urine are capable of stimulating an increase in IP3 in the
male VNO just as female urine is capable of stimulating an increase in
IP3 in female VNOs. This suggests that communication between members
of the same sex or of the opposite sex is mediated by increases in
IP3 as the second messenger.
Our study also shows that presentation of 2-heptanone and
2,5-dimethylpyrazine is able to stimulate the production of IP3 in
the female VNO but not the male VNO. When compared with the control, i.e.
treatment with water, 2,5-dimethylpyrazine and 2-heptanone were effective in
stimulating the production of IP3 in the female VNO (P <
0.05) but not the male VNO. This is an interesting observation that matches
behavioral data which show that these two compounds have specific pheromonal
effects in females and not males. Even though whole male or female urine is
capable of stimulating an increase in IP3 in males and females, our
result suggests that females may respond to specific chemicals within the
urine. This is unlike other systems such as in insects where the same chemical
compound solicits different pheromonal effects depending on the sex of the
recipient. We also noticed in our study that the production of IP3
in response to the individual urinary components was significantly higher than
the controls but much lower than the response from whole male and female urine.
This observation can be explained by the notion that urine contains a cocktail
of pheromones and that the high stimulus by urine is due to activation of a
vast majority of pheromone receptors coupled to the IP3 pathway. Our
biochemical results complement behavioral studies that have shown that
2-heptanone which is present in both male and female urine extends the estrus
cycle whereas 2,5-dimethylpyrazine present in only female urine delays puberty
in females (Novotny,
2003).
The differences observed in behavioral responses of males and females
to a specific pheromone may be due to differences in central processing. A
pheromonal effect has to be conducted through the glomeruli of the AOB to the
amygdala and hypothalamus and an appropriate response initiated. Perhaps, it is
this sexual dimorphism that allows differences in the behavior responses to a
particular pheromone. Experiments using immediate-early gene (IEG) protein
expression as markers of neuronal activity have shown that chemical signals in
soiled bedding stimulate a sexually dimorphic pattern of c-fos protein
immunoreactivity in central sites along the VNO projection pathway (Bakker et al., 1996;
Kelliher et al.,
1998;
Halem et al.,
1999, 2001). This explanation is highly unlikely in our case since
these two compounds were incapable of stimulating the male VNO.
In most sensory systems, sex differences in perception begin at the
sensory receptor. Here we have shown that the vomeronasal organ responds to
urinary stimuli in a sex dependent manner. This is important in coordinating
social and reproductive behaviors. Sex differences in the VNO response to
pheromones could reflect differences in the distribution of VNO receptor
subtypes (Herrada and Dulac,
1997). On the other hand, the differences may be due to sex
dimorphisms in the size of the VNO and number of neurons (Segovia and Guillamon, 1982) or to sex
differences in steroid-sensitive centrifugal inputs mediating the VNO response
to pheromones (Halem et al.,
2001).
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This work was supported by grants from the National Institutes of Health (GM08219 and P20 MD000547-1) to K.S.W.
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Accepted August 6, 2004
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