10.1. INTRODUCTION

In most species, there are two chemosensory systems, both located in the nasal cavity but physiologically and anatomically distinct (Figure 10.1). The main olfactory epithelium (MOE) is principally involved in the airborne odor perception, whereas the vomeronasal organ (VNO) of Jacobson in the detection of pheromones that are chemical compounds secreted or excreted by individuals of the same species (conspecifics) (Dulac & Torello 2003; Tirindelli et al. 2009). Deficits in social and reproductive behavior are marked in animals underlying the surgical removal of the VNO but also the chemical inactivation of the MOE (Kiyokawa et al. 2007; Kolunie & Stern 1995; Leypold et al. 2002; Wysocki & Lepri 1991). Furthermore, there is evidence that two olfactory structures, namely the septal organ of Masera and the Grueneberg ganglion also contribute to pheromone detection (Ma 2007; Roppolo et al. 2006; Tirindelli et al. 2009) (Figure 10.1).

FIGURE 10.1

Chemosensory systems sensing pheromones. The main olfactory system (MOE) and the vomeronasal system (VNO) together with the septal organ of Masera (SO) and the Grueneberg ganglion (GG) are implicated in pheromone detection. Projections of sensory neurons (more...)

Primary sensory VNO neurons (VSNs) send axons to mitral cells in the glomerular region of the accessory olfactory bulb (AOB), whereas olfactory neurons (OSNs) to the mitral cells of the main olfactory bulb (MOB) (Baum & Kelliher 2009; Clapham & Neer 1997) (Figure 10.1). The chemosensory neurons of the VNO and MOE are equipped with specific receptors that activate distinct molecular cascades and mediate sociosexual behaviors (Del Punta et al. 2002; Stowers et al. 2002).

The anatomical components of the VNO firstly developed in a tetrapod ancestor and led to the appearance of a rudimentary structure in amphibians that became highly organized in Squamata and in many mammalian orders as Didelphimorphia, Rodentia, and in primates (prosimians and New World monkeys). In contrast, VNO is virtually absent in birds, bats, Old World monkeys, apes, and humans (Dennis et al. 2004; Grus et al. 2005; Shi & Zhang 2007; Smith et al. 2005; Zhao et al. 2011) (Figure 10.2a).

FIGURE 10.2

(a) The phylogenetic tree of mammals. Mammals comprise about 5400 species that are distributed in six superorders including Euarchontoglires (Rodentia, Lagomorpha, primates), Laurasiatheria (Artiodactyla, Carnivora, Perissodactyla, and Chiroptera), Xenarthra (more...)

In Didelphimorphia, Lagomorpha, and Rodentia, the VNO chemosensory epithelium presents two separate neuronal layers (apical and basal) characterized by the expression of different G protein subunits and receptors (Young & Trask 2007). Apical and basal neurons project to two distinct regions (anterior and posterior) of the AOB. From the AOB, the majority of the centripetal projections of the apical and basal neurons remain segregated in the amygdala and hypothalamus (Martinez-Marcos 2009; Yoon et al. 2005).

In other mammalian orders (Carnivora) the dichotomic organization of the vomeronasal projections is not well defined or even absent (Artiodactyla) (Dennis et al. 2003).

10.2. PHEROMONE RECEPTORS

The molecular organization of the rodent vomeronasal neuroepithelium in apical and basal neurons is based on the specific expression pattern of two transduction molecules, G protein Gα_i2 and Gα_o, and two distinct superfamilies of pheromone receptors, type-1 vomeronasal receptors (V1Rs) (Dulac & Axel 1995) and type-2 vomeronasal receptors (V2Rs) (Herrada & Dulac 1997; Matsunami & Buck 1997; Ryba & Tirindelli 1997).

Gα_i2 is expressed in the apical neurons and colocalizes with V1Rs, whereas Gα_o coexpresses with V2Rs in the basal neurons (Rodriguez et al. 2002).

Although both are G protein coupled receptors, V2Rs differ from V1Rs for the presence of introns in the genes and for the long N-terminal extracellular region that reflects the chemical properties of their ligands (Boschat et al. 2002; Emes et al. 2004; Ishii & Mombaerts 2008; Isogai et al. 2011; Kimoto et al. 2005). Furthermore, V1Rs and V2Rs display a differential evolutionary expansion in terrestrial vertebrates (Brykczynska et al. 2013; Dong et al. 2012; Grus et al. 2007; Liberles et al. 2009; Ryu et al. 2013; Yang & Shi 2010) (Figure 10.2a, b, and d).

However, although only V1Rs and V2Rs have been proved to respond to pheromones, the vomeronasal expression of a third class of putative pheromone receptors, formyl-peptide receptors (VNO-FPRs), was recently demonstrated (Boschat et al. 2002; Del Punta et al. 2002; Dulac & Torello 2003). FPRs are expressed in both the apical and basal regions of the VNOs of some murine rodents and may represent a link between the G_i and G_o subsystems (Liberles et al. 2009; Riviere et al. 2009).

Additionally, basal VNO neurons express a family of nonclassical molecules of the major histocompatibility complex (H2-Mv) (Ishii & Mombaerts 2008; Leinders-Zufall et al. 2009; Loconto et al. 2003). The role of the H2-Mv complex in the VNO is still debated and whether these molecules are to be considered as pheromone receptors remains to be demonstrated (Ishii & Mombaerts 2008; Loconto et al. 2003).

10.2.1. V1Rs

V1Rs are already present in lower vertebrate (fish and frog) genomes (Date-Ito et al. 2008; Grus & Zhang 2009; Hashiguchi et al. 2008; Saraiva & Korsching 2007). In mammals, V1Rs expansion occurred independently from a small number of ancestral genes that pseudogenized or completely disappeared in the Squamata order (Young et al. 2010). Remarkable gene duplications occurred in the Rodentia order with the generation of several subfamilies (Grus & Zhang 2004; Rodriguez et al. 2002) (Figure 10.2b).

The V1R repertoire is characterized by a rapid gene turnover, significant variation of the size among species, positive selection, and lineage-specific clustering (Emes et al. 2004; Shi et al. 2005; Young et al. 2005).

V1R genes diverge among mammals following species-specific duplications that resulted in the formation of distinct clades with the occurrence of very few orthologs only present in closely related species (Park et al. 2011).

The high rate of duplication led to a large degree of pseudogenization also in species that present a considerable number of intact V1R genes and a well-developed VNO. In total, of about 7000 V1R-like sequences that have been identified in 37 species, only 1809 represent functional genes (Young et al. 2010).

In general, V1R genes expanded in mammals that possess an highly organized VNO, such as platypus (283 genes), opossum (98), mouse (239), rat (109), rabbit (159), and mouse lemur (105), whereas they are absent or pseudogenized in Old World monkeys, apes, and humans that possess a vestigial and presumably non-functional VNO (Brykczynska et al. 2013; Grus & Zhang 2004; Grus et al. 2007; Hohenbrink et al. 2013; Rodriguez et al. 2002; Young et al. 2010) (Figure 10.2a). Surprisingly, the dog (Carnivora) genome displays a very small repertoire of intact V1R genes (9) in contrast to a much larger number of pseudogenes (38); a deterioration that does not seem to be correlated with the selective pressure that occurred during domestication, since the wolf genome presents homologous copies of the dog pseudogenes (Young et al. 2010). Interestingly, and in contrast to what was previously described, ruminant species such as cow, sheep, and goat evolved a significant number of V1R orthologs that are expressed in both the MOE and VNO. In cow, 70% of V1R genes has orthologs in the cross-species ruminant counterpart in contrast to the 9% of the mouse V1R orthologs identified in rat (mouse-rat are phylogenetically much closer species than cow-sheep) (Grus et al. 2005; Ohara et al. 2009) (Figure 10.2b). These unusual findings might suggest a possible involvement of both VNO and MOE in the detection of V1R ligands. Moreover, in these ruminant species (herbivores) V1Rs may also subserve to other functions rather than purely pheromonal. For instance, ruminant V1R orthologs could be involved in the detection of the same or closely related chemical cues as heterospecific odorants (allomones) (Ohara et al. 2009; Takigami et al. 2000; Wakabayashi et al. 2002).

In rodents, there are indications that V1Rs originated from an ancestor that probably possessed very few V1R genes. The majority of these genes duplicated independently generating a species-specific lineage. Lineage specificity appears so rigorous that a limited degree of orthology is only detectable in very closely related species such as Mus spretus and Mus musculus that diverged 1 million years ago (Grus & Zhang 2004; Park et al. 2011; Young et al. 2010).

The very large human V1R repertoire shows an almost complete pseudogenization (about 200 pseudogenes and only four intact genes) that occurred before the separation of hominoids (apes and humans) from Old World monkeys and was probably linked to the complete loss of the VNO (Zhang & Webb 2004).

Mouse V1Rs represent the first superfamily of pheromone receptors that have been discovered, and as with olfactory receptors, they show a monogenic expression that means that each VNO neuron expresses only one receptor type. In this murine species, V1Rs account for about 250 functionally receptors expressed in the apical VNO neurons. V1Rs are organized in 12 phylogenetically isolated subfamilies (a to k) with an identity ranging from 40% to 99% within subfamilies and from 15% to 40% between subfamilies (DelPunta et al. 2000; Rodriguez et al. 2002) (Figure 10.2b).

Positive selection (a ratio between nonsynonymous and synonymous amino acid substitution greater than 1) that is an index of a fast gene evolution has been reported acting on the V1R repertoire (Grus & Zhang 2004; Hohenbrink et al. 2012, 2013; Mundy & Cook 2003; Wyckoff et al. 2000). Thus, the rapid diversification of the mouse V1Rs developed in association with an increasingly high predominance of the pheromone-mediated communication. As a consequence, if a pheromone blend evolved rapidly and accumulated chemical changes, the V1Rs recognition system might have been subjected to a strong selective pressure (Shi et al. 2005).

In particular, the analysis of the sequences corresponding to the transmembrane domain 2 and the extracellular loops I and II of these receptors has shown the highest variability within species in combination with a strong positive selection, suggesting that these regions are implicated in pheromone binding (Rodriguez 2004).

Investigations on V1R expressing neurons (apical) led to the identification of four candidate V1R ligands, 2-hepatanone, 6-hydroxyl-6-methyl-3-heptanone, n-pentylacetate and isobutylamine (Table 10.1). These molecules are detectable in the mouse urine and have shown to activate, in a very specific fashion, distinct V1Rs (Boschat et al. 2002).

TABLE 10.1

V1R and V2R Ligands and Their Suggested Function in Pheromonal Communication

In contrast, other V1Rs appear to respond to multiple chemical cues, some of which are also emitted by heterospecific animals (Isogai et al. 2011) (Table 10.1).

From these studies, it is possible to envisage that distinct subpopulations of apical neurons, presumably expressing different V1R subtypes, are tuned to detect either individual or multiple pheromonal molecules (Boschat et al. 2002; Isogai et al. 2011).

A single behavioral study on deficient mice for V1R genes has provided clues on the function of some of these receptors. Mice bearing the complete deletion of the V1Ra and V1Rb gene clusters display a significant reduction of male-to-male and maternal aggressiveness compared to controls. In addition, these mutant mice do not show electrophysiological responses to 6-hydroxyl-6-methyl-3-heptanone, n-pentylacetate and isobutylamine (Del Punta et al. 2002).

In conclusion, a reliable correlation between the size of the V1R repertoire and the habits, the ecological system, and the sociosexual behavior of each species is difficult to establish. There appears to be a weak association between the size of intact V1R genes in terricolous mammals and two ecological factors: spatial (nest-living and open-living behavior) and rhythms (diurnal and nocturnal) activity (Wang et al. 2010). With few but significant exceptions (tenrec, sloth, squirrel, and pika), nest-living and nocturnal mammals (mouse, rat, kangaroo rat, rabbit, and lemur) seem to require more functional genes than open-living and diurnal mammals (among which horse, cow, and apes) perhaps in order to explore restricted and dark environments (Grus et al. 2005, 2007; Wang et al. 2010).

10.2.3. FPRs

FPRs belong to the seven-transmembrane domain G protein coupled receptor superfamily and are present in tissues and cell lines involved in the immune response as lymphocytes, monocytes, macrophages, and microglia of most mammalian genera (Le et al. 2002; Migeotte et al. 2006); however, recent findings indicate that a murine subclass of FPRs are specifically expressed in the VNO (Liberles et al. 2009; Riviere et al. 2009) (Table 10.2).

TABLE 10.2

Expression of FPRs in Humans and Mice

The phylogenetic tree of FPRs suggests a very complex distribution of these receptors. FPRs represent a monophyletic group divided into three clades, FPR1, FPRL1, and FPRL2 (Yang & Shi 2010).

FPR1s are phylogenetically the most ancient as a related gene is present in the lamprey (Petromyzontiformes) genome (Figure 10.2e). In placental mammals FPR1 orthologs are present in many species irrespective of the development of a functional VNO. Interestingly, Laurasiatheria, which include Carnivora (cat and dog), Perissodactyla (horse), Artiodactyla (cow, pig, and sheep), and Chiroptera (bat), have probably lost the fpr1 genes (and pseudogenes) (Figure 10.2e). Didelphimorpha (opossum) possess fpr-like genes with 40% identity with respect to placental mammals.

The second FPR clade, FPRL1, which is phylogenetically more recent, includes receptors already present in Laurasiatheria that forms a lineage-specific gene cluster that was erroneously regarded as VNO specific, since family Muridae predominantly express these receptors in the VNO.

The third FPR clade, FPRL2, which presumably arose from the duplication of the FPR1 gene, appears to be expanded in primates, forming a lineage-specific clade with a homology of 85%–99% between species (Figure 10.2e).

In mice, FPRL1s represent a rodent specific branch that is characterized by seven protein coding genes located on chromosome 17: Fpr-rs1, Fpr-rs2, Fpr-rs3, Fpr-rs4, Fpr-rs6, and Fpr-rs7 (Fpr-rs5 is a pseudogene). These genes show an identity that ranges from 67% to 96%, and with the exclusion of Fpr-rs2, they appear to be exclusively expressed in the VNO. In rat, a similar expansion occurred with the presence of seven functional genes that show a one-to-one ortology with the mouse genes. Moreover, VNO-FPRs appear to be already established in other rodent species of different genera as rat and gerbil (Liberles et al. 2009; Riviere et al. 2009). Thus, it is likely that VNO-FPRs were already present in a Muridae ancestor (Figure 10.2a,e).

FPR-rs3, FPR-rs4, FPR-rs6, and FPR-rs7 are exclusively or predominantly expressed in the apical neurons and coexpressed with Gα_i2. In contrast, FPR-rs1 is located more basally and is coexpressed with Gα_o (Liberles et al. 2009). The FPR expression pattern appears punctuate and therefore similar to that observed for V1Rs and for most members of V2Rs, thus suggesting a monogenic transcription for these genes (Dulac & Axel 1995; Herrada & Dulac 1997; Ryba & Tirindelli 1997). Since there is no evidence of a coexpression of FRPs with V1Rs or V2Rs, it is likely that specific subsets of VNO neurons exclusively express FPRs (Liberles et al. 2009; Riviere et al. 2009; Yang & Shi 2010). The functional role of both non-VNO and VNO-FPRs is still unclear although a conspicuous number of FPRs agonists and antagonists has been identified (Seifert & Wenzel-Seifert 2003; Thoren et al. 2010).

Human and mouse FPRs are activated by viral and bacterial products (Bae et al. 2003a,b). The most effective ligands of almost all FPRs is the bacterial N-formyl-methionyl-leucyl-phenylalanine (fMLF) that triggers several biological immunological functions in neutrophils, monocytes, and macrophages (Boulay et al. 1990; Cevik-Aras et al. 2012; Le et al. 2002). In particular, the lack of FPR1 gene causes an increase of Listeria monocytogenes sensitivity in mouse (Gao et al. 1999).

As for VNO-FPRs, FPR-rs1 was reportedly identified to be specific to lipoxin A4 (it was in fact named as LXA4R9), a lipid mediator generated at the site of inflammation that both regulates the transport of intermediates between platelets, neutrophils, and natural killer cells and lymphocytes activation in the chronic inflammations (Migeotte et al. 2006; Takano et al. 1997). In contrast, cloned FPR-rs1 and 3 predominantly respond to the cathelin-related antimicrobial peptide (CRAMP) that acts as chemotactic factor in vivo. FPR-rs6 senses fMLF whereas FPR-rs4 and 7 detect both ligands. Moreover, FPR-rs4 also responds to lipoxin A4 (Riviere et al. 2009) (Table 10.1).

Similarly to all other FPRs, each VNO-FPR probably responds to a large array of ligands, most of which have not yet been characterized. Moreover, VNO-FPRs responding to ligands do not show particular selectivity for these receptors, being effective at a similar concentration on several FPR subtypes of different species. This observation appears to contrast with the most recent phylogenetic studies on FPR genes that aim at concluding that the selective pressure exclusively acting on VNO-FPRs rather than all other FPRs is possibly linked to the functional transition from host defense (FPRL1) to vomeronasal chemosensation (VNO-FPRs) (Liberles et al. 2009).

In light of these findings it appears very difficult to define a pheromonal role for these receptors. One possibility is that VNO-FPRs may exploit the specific function of detecting compounds specifically synthesized by the bacterial flora inhabiting the secretions of conspecific or heterospecific animals, thus allowing individual identification (Riviere et al. 2009).

As a summary of vomeronasal receptors, it is possible to envisage that V1Rs recognize volatile molecules also produced by sympatric species whereas V2Rs respond to excretory proteins and peptides exclusively expressed by individuals of the same species. In contrast, FPRs sense microbial peptides that, as suggested above, may also be indirectly involved in both species or individual recognition (Del Punta et al. 2002; Chamero et al. 2007; Isogai et al. 2011; Kimoto et al. 2005; Leinders-Zufall et al. 2000, 2004; Liberles et al. 2009; Riviere et al. 2009).

10.3. SIGNAL TRANSDUCTION MECHANISMS

Binding of pheromones to vomeronasal receptors initiates a transduction cascade that produces an excitatory response. Pheromonal stimuli cause membrane depolarization and increase the action potential firing rate and the intracellular calcium concentration in VSNs (Celsi et al. 2012; Holy et al. 2000; Inamura & Kashiwayanagi 2000; Leinders-Zufall et al. 2000; Nodari et al. 2008; Shimazaki et al. 2006; Spehr et al. 2002). Despite several similarities in response to stimuli are shared between vomeronasal and olfactory sensory neurons, the transduction mechanisms used by these chemosensory cells are distinct (Berghard & Buck 1996; Wu et al. 1996).

10.3.1. G Proteins

As previously described, the two subsets of apical and basal VSNs expressing V1Rs or V2Rs and FPRs also express different G proteins (Figure 10.3). Berghard and Buck identified two types of G protein α subunits in basal, Gα_o, and apical, Gα_i2, mouse VSNs (Berghard & Buck 1996). Ultrastructural studies showed that both Gα_o and Gα_i2 are located in the microvilli where the vomeronasal transduction occurs (Menco et al. 2001). The activation of GPRCs causes the release of the βγ complex of the heterotrimeric G protein G_o and G_i2 responsible for phospholipase C (PLC) activation, indicating that β and γ subunits play a pivotal role in vomeronasal sensory transduction (Clapham & Neer 1997). Runnenburger and colleagues reported that one type of β subunit, β₂, is expressed in the vomeronasal sensory epithelium and that an antibody against β₂ caused a reduction of IP₃ production in microvilli extracts stimulated with urine (Runnenburger et al. 2002). Moreover, two γ subunits, γ₂ and γ₈, are expressed in VSNs (Runnenburger et al. 2002; Ryba & Tirindelli 1995; Tirindelli & Ryba 1996). Interestingly, the expression of the γ₂ subunit is confined to apical neurons, whereas the γ₈ subunit is preferentially expressed in the basal neuronal population. Treatment of microvilli extract with specific antibodies against γ₂ and γ₈ reduced the production of IP₃ upon urine stimulation, suggesting that both subunits play a role in sensory transduction (Runnenburger et al. 2002).

FIGURE 10.3

Signaling molecules involved in the transduction of pheromonal stimuli. (a) The binding of pheromones to V1R receptors in the microvilli activates PLC through the G protein Goβ₂γ₈. PLC produces the second messengers DAG and IP₃. The gating (more...)

The functional role of G proteins expressed in the VNO has been investigated in knockout mice. Gα_i2-deficient animals produced a severe postnatal neurodegeneration of apical VSNs, causing the death of about 50% of VSNs and a consequent reduction of about 50% of the glomerular layer of the anterior AOB (Norlin et al. 2003). Using c-Fos as a marker for neuronal activity, it has been reported that the lack of Gα_i2 caused a fivefold reduction of c-Fos expression in the anterior AOB of male mice exposed to bedding soiled by female mice. Behavioral studies have revealed that male mice display normal sexual behaviors whereas females present a strong reduction of maternal aggression, indicating that Gα_i2-expressing VSNs mediated these processes (Norlin et al. 2003). Direct measurements of responses to stimuli of VSNs lacking Gα_i2 would help clarify its role in sensory transduction, but at present they are not available.

The role of G proteins in survival of VSNs was confirmed also in conditional and general knockout mice for Gα_o: a severe postnatal neurodegeneration of basal VSNs caused the death of about 50% VSNs (Chamero et al. 2011; Tanaka et al. 1999). Chamero and colleagues (2011) measured the responses of VSNs with electrovomeronasogram (EVG) recordings and Ca²⁺ imaging assay. These authors reported that VSNs from Gα_o knockout mice did not respond to stimulation with known V2R ligands, such as MHC class I peptides, ESPs, and MUPs, and with FPR-rs1 agonists. In contrast, Gα_o-deficient VSNs present normal responses to V1R ligands such as 2-heptanone and isobutylamine and to FPR-rs2-5 (Chamero et al. 2011). Furthermore, behavioral studies showed a decreased male-to-male aggressiveness mediated by MHC class I peptides and MUPs, and surprisingly, a reduction of maternal aggression, a behavior that is also mediated by V2R-Gα_i2-expressing neurons (Chamero et al. 2011).

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