Abstract
Communication between individuals is critical for species survival, reproduction, and expansion. Most terrestrial species, with the exception of humans who predominantly use vision and phonation to create their social network, rely on the detection and decoding of olfactory signals, which are widely known as pheromones. These chemosensory cues originate from bodily fluids, causing attractive or avoidance behaviors in subjects of the same species. Intraspecific pheromone signaling is then crucial to identify sex, social ranking, individuality, and health status, thus establishing hierarchies and finalizing the most efficient reproductive strategies. Indeed, all these features require fine tuning of the olfactory systems to detect molecules containing this information. To cope with this complexity of signals, tetrapods have developed dedicated olfactory subsystems that refer to distinct peripheral sensory detectors, called the main olfactory and the vomeronasal organ, and two minor structures, namely the septal organ of Masera and the Grueneberg ganglion. Among these, the vomeronasal organ plays the most remarkable role in pheromone coding by mediating several behavioral outcomes that are critical for species conservation and amplification. In rodents, this organ is organized into two segregated neuronal subsets that express different receptor families. To some extent, this dichotomic organization is preserved in higher projection areas of the central nervous system, suggesting, at first glance, distinct functions for these two neuronal pathways. Here, I will specifically focus on this issue and discuss the role of vomeronasal receptors in mediating important innate behavioral effects through the recognition of pheromones and other biological chemosignals.
Similar content being viewed by others
References
Ahuja G, Reichel V, Kowatschew D, Syed AS, Kotagiri AK, Oka Y, Weth F, Korsching SI (2018) Overlapping but distinct topology for zebrafish V2R-like olfactory receptors reminiscent of odorant receptor spatial expression zones. BMC Genomics 19:383
Akiyoshi S, Ishii T, Bai Z, Mombaerts P (2018) Subpopulations of vomeronasal sensory neurons with coordinated coexpression of type 2 vomeronasal receptor genes are differentially dependent on Vmn2r1. Eur J Neurosci 47:887–900
Alioto TS, Ngai J (2006) The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids. BMC Genomics 7:309
Bacchini A, Gaetani E, Cavaggioni A (1992) Pheromone binding proteins of the mouse, Mus musculus. Experientia 48:419–421
Baum MJ, Kelliher KR (2009) Complementary roles of the main and accessory olfactory systems in mammalian mate recognition. Annu Rev Physiol 71:141–160
Belluscio L, Koentges G, Axel R, Dulac C (1999) A map of pheromone receptor activation in the mammalian brain. Cell 97:209–220
Ben-Shaul Y, Katz LC, Mooney R, Dulac C (2010) In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb. Proc Natl Acad Sci USA 107:5172–5177
Bhatnagar KP, Smith TD (2007) Light microscopic and ultrastructural observations on the vomeronasal organ of Anoura (Chiroptera: Phyllostomidae). Anat Rec (Hoboken) 290:1341–1354
Boehm U, Zou Z, Buck LB (2005) Feedback loops link odor and pheromone signaling with reproduction. Cell 123:683–695
Boillat M, Challet L, Rossier D, Kan C, Carleton A, Rodriguez I (2015) The vomeronasal system mediates sick conspecific avoidance. Curr Biol 25:251–255
Boschat C, Pelofi C, Randin O, Roppolo D, Luscher C, Broillet MC, Rodriguez I (2002) Pheromone detection mediated by a V1r vomeronasal receptor. Nat Neurosci 5:1261–1262
Brechbuhl J, Klaey M, Broillet MC (2008) Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 321:1092–1095
Breer H, Fleischer J, Strotmann J (2006) The sense of smell: multiple olfactory subsystems. Cell Mol Life Sci 63:1465–1475
Bruce HM (1959) An exteroceptive block to pregnancy in the mouse. Nature 184:105
Brykczynska U, Tzika AC, Rodriguez I, Milinkovitch MC (2013) Contrasted evolution of the vomeronasal receptor repertoires in mammals and squamate reptiles. Genome Biol Evol 5:389–401
Bufe B, Schumann T, Kappl R, Bogeski I, Kummerow C, Podgorska M, Smola S, Hoth M, Zufall F (2015) Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a new mechanism for sensing pathogens. J Biol Chem 290:7369–7387
Bufe B, Schumann T, Zufall F (2012) Formyl peptide receptors from immune and vomeronasal system exhibit distinct agonist properties. J Biol Chem 287:33644–33655
Bufe B, Teuchert Y, Schmid A, Pyrski M, Perez-Gomez A, Eisenbeis J, Timm T, Ishii T, Lochnit G, Bischoff M, Mombaerts P, Leinders-Zufall T, Zufall F (2019) Bacterial MgrB peptide activates chemoreceptor Fpr3 in mouse accessory olfactory system and drives avoidance behaviour. Nat Commun 10:4889
Cavaliere RM, Silvotti L, Percudani R, Tirindelli R (2020) Female mouse tears contain an anti-aggression pheromone. Sci Rep 10:2510
Celsi F, D’Errico A, Menini A (2012) Responses to sulfated steroids of female mouse vomeronasal sensory neurons. Chem Senses 37:849–858
Chamero P, Katsoulidou V, Hendrix P, Bufe B, Roberts R, Matsunami H, Abramowitz J, Birnbaumer L, Zufall F, Leinders-Zufall T (2011) G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice. Proc Natl Acad Sci USA 108:12898–12903
Chamero P, Leinders-Zufall T, Zufall F (2012) From genes to social communication: molecular sensing by the vomeronasal organ. Trends Neurosci 35:597–606
Chamero P, Marton TF, Logan DW, Flanagan K, Cruz JR, Saghatelian A, Cravatt BF, Stowers L (2007) Identification of protein pheromones that promote aggressive behaviour. Nature 450:899–902
Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJ (2000) T2Rs function as bitter taste receptors. Cell 100:703–711
Chen AX, Yan JJ, Zhang W, Wang L, Yu ZX, Ding XJ, Wang DY, Zhang M, Zhang YL, Song N, Jiao ZL, Xu C, Zhu SJ, Xu XH (2020) Specific Hypothalamic Neurons Required for Sensing Conspecific Male Cues Relevant to Inter-male Aggression. Neuron
Cong X, Zheng Q, Ren W, Cheron JB, Fiorucci S, Wen T, Zhang C, Yu H, Golebiowski J, Yu Y (2019) Zebrafish olfactory receptors ORAs differentially detect bile acids and bile salts. J Biol Chem 294:6762–6771
Cutler G, Marshall LA, Chin N, Baribault H, Kassner PD (2007) Significant gene content variation characterizes the genomes of inbred mouse strains. Genome Res 17:1743–1754
Dahlgren C, Gabl M, Holdfeldt A, Winther M, Forsman H (2016) Basic characteristics of the neutrophil receptors that recognize formylated peptides, a danger-associated molecular pattern generated by bacteria and mitochondria. Biochem Pharmacol 114:22–39
Date-Ito A, Ohara H, Ichikawa M, Mori Y, Hagino-Yamagishi K (2008) Xenopus V1R vomeronasal receptor family is expressed in the main olfactory system. Chem Senses 33:339–346
Del Punta K, Leinders-Zufall T, Rodriguez I, Jukam D, Wysocki CJ, Ogawa S, Zufall F, Mombaerts P (2002) Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes. Nature 419:70–74
Del Punta K, Puche A, Adams NC, Rodriguez I, Mombaerts P (2002) A divergent pattern of sensory axonal projections is rendered convergent by second-order neurons in the accessory olfactory bulb. Neuron 35:1057–1066
Del Punta K, Rothman A, Rodriguez I, Mombaerts P (2000) Sequence diversity and genomic organization of vomeronasal receptor genes in the mouse. Genome Res 10:1958–1967
DeMaria S, Berke AP, Van Name E, Heravian A, Ferreira T, Ngai J (2013) Role of a ubiquitously expressed receptor in the vertebrate olfactory system. J Neurosci 33:15235–15247
Demir E, Li K, Bobrowski-Khoury N, Sanders JI, Beynon RJ, Hurst JL, Kepecs A, Axel R (2020) The pheromone darcin drives a circuit for innate and reinforced behaviours. Nature 578:137–141
Dennis JC, Allgier JG, Desouza LS, Eward WC, Morrison EE (2003) Immunohistochemistry of the canine vomeronasal organ. J Anat 203:329–338
Dey S, Chamero P, Pru JK, Chien MS, Ibarra-Soria X, Spencer KR, Logan DW, Matsunami H, Peluso JJ, Stowers L (2015) Cyclic Regulation of sensory perception by a female hormone alters behavior. Cell 161:1334–1344
Dey S, Matsunami H (2011) Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors. Proc Natl Acad Sci USA 108:16651–16656
Dietschi Q, Tuberosa J, Rosingh L, Loichot G, Ruedi M, Carleton A, Rodriguez I (2017) Evolution of immune chemoreceptors into sensors of the outside world. Proc Natl Acad Sci USA 114:7397–7402
Dinka H, Le MT, Ha H, Cho H, Choi MK, Choi H, Kim JH, Soundarajan N, Park JK, Park C (2015) Analysis of the vomeronasal receptor repertoire, expression and allelic diversity in swine. Genomics 107:208–215
Dittrich K, Kuttler J, Hassenklover T, Manzini I (2016) Metamorphic remodeling of the olfactory organ of the African clawed frog, Xenopus laevis. J Comp Neurol 524:986–998
Dong D, Jin K, Wu X, Zhong Y (2012) CRDB: database of chemosensory receptor gene families in vertebrate. PLoS ONE 7:e31540
Doving KB, Trotier D (1998) Structure and function of the vomeronasal organ. J Exp Biol 201:2913–2925
Doyle WI, Dinser JA, Cansler HL, Zhang X, Dinh DD, Browder NS, Riddington IM, Meeks JP (2016) Faecal bile acids are natural ligands of the mouse accessory olfactory system. Nat Commun 7:11936
Dulac C, Axel R (1995) A novel family of genes encoding putative pheromone receptors in mammals. Cell 83:195–206
Eisthen HL (1992) Phylogeny of the vomeronasal system and of receptor cell types in the olfactory and vomeronasal epithelia of vertebrates. Microsc Res Tech 23:1–21
Ferrero DM, Lemon JK, Fluegge D, Pashkovski SL, Korzan WJ, Datta SR, Spehr M, Fendt M, Liberles SD (2011) Detection and avoidance of a carnivore odor by prey. Proc Natl Acad Sci USA 108:11235–11240
Ferrero DM, Moeller LM, Osakada T, Horio N, Li Q, Roy DS, Cichy A, Spehr M, Touhara K, Liberles SD (2013) A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system. Nature 502:368–371
Fu X, Yan Y, Xu PS, Geerlof-Vidavsky I, Chong W, Gross ML, Holy TE (2015) A molecular code for identity in the vomeronasal system. Cell 163:1–11
Gliem S, Syed AS, Sansone A, Kludt E, Tantalaki E, Hassenklover T, Korsching SI, Manzini I (2013) Bimodal processing of olfactory information in an amphibian nose: odor responses segregate into a medial and a lateral stream. Cell Mol Life Sci 70:1965–1984
Gonzalez A, Morona R, Lopez JM, Moreno N, Northcutt RG (2010) Lungfishes, like tetrapods, possess a vomeronasal system. Frontiers in neuroanatomy 4:130
Graubert TA, Cahan P, Edwin D, Selzer RR, Richmond TA, Eis PS, Shannon WD, Li X, McLeod HL, Cheverud JM, Ley TJ (2007) A high-resolution map of segmental DNA copy number variation in the mouse genome. PLoS Genet 3:e3
Grus WE, Shi P, Zhang J (2007) Largest vertebrate vomeronasal type 1 receptor gene repertoire in the semiaquatic platypus. Mol Biol Evol 24:2153–2157
Grus WE, Shi P, Zhang YP, Zhang J (2005) Dramatic variation of the vomeronasal pheromone receptor gene repertoire among five orders of placental and marsupial mammals. Proc Natl Acad Sci USA 102:5767–5772
Grus WE, Zhang J (2008) Distinct evolutionary patterns between chemoreceptors of 2 vertebrate olfactory systems and the differential tuning hypothesis. Mol Biol Evol 25:1593–1601
Grus WE, Zhang J (2009) Origin of the genetic components of the vomeronasal system in the common ancestor of all extant vertebrates. Mol Biol Evol 26:407–419
Haga-Yamanaka S, Ma L, He J, Qiu Q, Lavis LD, Looger LL, Yu CR (2014) Integrated action of pheromone signals in promoting courtship behavior in male mice. eLife 3:e03025
Haga S, Hattori T, Sato T, Sato K, Matsuda S, Kobayakawa R, Sakano H, Yoshihara Y, Kikusui T, Touhara K (2010) The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 466:118–122
Halpern M, Martinez-Marcos A (2003) Structure and function of the vomeronasal system: an update. Prog Neurobiol 70:245–318
Halpern M, Shapiro LS, Jia C (1995) Differential localization of G proteins in the opossum vomeronasal system. Brain Res 677:157–161
Harvey S, Jemiolo B, Novotny M (1989) Pattern of volatile compounds in dominant and subordinate male mouse urine. J Chem Ecol 15:2061–2072
Hattori T, Osakada T, Masaoka T, Ooyama R, Horio N, Mogi K, Nagasawa M, Haga-Yamanaka S, Touhara K, Kikusui T (2017) Exocrine gland-secreting peptide 1 is a key chemosensory signal responsible for the Bruce effect in mice. Curr Biol 27:3197–3201
Hattori T, Osakada T, Matsumoto A, Matsuo N, Haga-Yamanaka S, Nishida T, Mori Y, Mogi K, Touhara K, Kikusui T (2016) Self-exposure to the male pheromone ESP1 enhances male aggressiveness in mice. Curr Biol 26:1229–1234
Herrada G, Dulac C (1997) A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90:763–773
Hofmann AF, Hagey LR, Krasowski MD (2010) Bile salts of vertebrates: structural variation and possible evolutionary significance. J Lipid Res 51:226–246
Hohenbrink P, Mundy NI, Zimmermann E, Radespiel U (2013) First evidence for functional vomeronasal 2 receptor genes in primates. Biol Lett 9:20121006
Hunnicutt KE, Tiley GP, Williams RC, Larsen PA, Blanco MB, Rasoloarison RM, Campbell CR, Zhu K, Weisrock DW, Matsunami H, Yoder AD (2020) Comparative genomic analysis of the pheromone receptor class 1 family (V1R) reveals extreme complexity in mouse lemurs (genus, Microcebus) and a chromosomal hotspot across mammals. Genome Biol Evol 12:3562–3579
Ibrahim D (2018) Immunolocalization of receptor and chemoreceptor modules in the sheep vomeronasal organ. Cells Tissues Organs 205:85–92
Ishii KK, Osakada T, Mori H, Miyasaka N, Yoshihara Y, Miyamichi K, Touhara K (2017) A labeled-line neural circuit for pheromone-mediated sexual behaviors in mice. Neuron 95:1–15
Ishii T, Hirota J, Mombaerts P (2003) Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr Biol 13:394–400
Ishii T, Mombaerts P (2008) Expression of nonclassical class I major histocompatibility genes defines a tripartite organization of the mouse vomeronasal system. J Neurosci 28:2332–2341
Ishii T, Mombaerts P (2011) Coordinated coexpression of two vomeronasal receptor V2R genes per neuron in the mouse. Mol Cell Neurosci 46:397–408
Isogai Y, Si S, Pont-Lezica L, Tan T, Kapoor V, Murthy VN, Dulac C (2011) Molecular organization of vomeronasal chemoreception. Nature 478:241–245
Isogai Y, Wu Z, Love MI, Ahn MH, Bambah-Mukku D, Hua V, Farrell K, Dulac C (2018) Multisensory logic of infant-directed aggression by males. Cell 175:1827–1841
Jacobson L, Trotier D, Doving KB (1998) Anatomical description of a new organ in the nose of domesticated animals by Ludvig Jacobson (1813). Chem Senses 23:743–754
Jemiolo B, Andreolini F, Xie TM, Wiesler D, Novotny M (1989) Puberty-affecting synthetic analogs of urinary chemosignals in the house mouse, Mus domesticus. Physiol Behav 46:293–298
Ji Y, Zhang Z, Hu Y (2009) The repertoire of G-protein-coupled receptors in Xenopus tropicalis. BMC Genomics 10:263
Jia C, Halpern M (1996) Subclasses of vomeronasal receptor neurons: differential expression of G proteins (Gi alpha 2 and G(o alpha)) and segregated projections to the accessory olfactory bulb. Brain Res 719:117–128
Jiao H, Hong W, Nevo E, Li K, Zhao H (2019) Convergent reduction of V1R genes in subterranean rodents. BMC Evol Biol 19:176
Jones G, Teeling EC, Rossiter SJ (2013) From the ultrasonic to the infrared: molecular evolution and the sensory biology of bats. Front Physiol 4:117
Kahan A, Ben-Shaul Y (2016) Extracting behaviorally relevant traits from natural stimuli: benefits of combinatorial representations at the accessory olfactory bulb. PLoS Comput Biol 12:e1004798
Karlson P, Luscher M (1959) Pheromones’: a new term for a class of biologically active substances. Nature 183:55–56
Kaur AW, Ackels T, Kuo TH, Cichy A, Dey S, Hays C, Kateri M, Logan DW, Marton TF, Spehr M, Stowers L (2014) Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors. Cell 157:676–688
Kelliher KR (2007) The combined role of the main olfactory and vomeronasal systems in social communication in mammals. Horm Behav 52:561–570
Kelliher KR, Spehr M, Li XH, Zufall F, Leinders-Zufall T (2006) Pheromonal recognition memory induced by TRPC2-independent vomeronasal sensing. Eur J Neurosci 23:3385–3390
Kimchi T, Xu J, Dulac C (2007) A functional circuit underlying male sexual behaviour in the female mouse brain. Nature 448:1009–1014
Kimoto H, Haga S, Sato K, Touhara K (2005) Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons. Nature 437:898–901
Kimoto H, Sato K, Nodari F, Haga S, Holy TE, Touhara K (2007) Sex- and strain-specific expression and vomeronasal activity of mouse ESP family peptides. Curr Biol 17:1879–1884
Kobayakawa K, Kobayakawa R, Matsumoto H, Oka Y, Imai T, Ikawa M, Okabe M, Ikeda T, Itohara S, Kikusui T, Mori K, Sakano H (2007) Innate versus learned odour processing in the mouse olfactory bulb. Nature 450:503–508
Kurzweil VC, Getman M, Green ED, Lane RP (2009) Dynamic evolution of V1R putative pheromone receptors between Mus musculus and Mus spretus. BMC Genomics 10:74
Ladewig J, Price EO, Hart BL (1980) Flehmen in male goats: role in sexual behavior. Behav Neural Biol 30:312–322
Lee D, Kume M, Holy TE (2019) Sensory coding mechanisms revealed by optical tagging of physiologically defined neuronal types. Science 366:1384–1389
Leinders-Zufall T, Brennan P, Widmayer P, S PC, Maul-Pavicic A, Jager M, Li XH, Breer H, Zufall F, Boehm T, (2004) MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306:1033–1037
Leinders-Zufall T, Ishii T, Chamero P, Hendrix P, Oboti L, Schmid A, Kircher S, Pyrski M, Akiyoshi S, Khan M, Vaes E, Zufall F, Mombaerts P (2014) A family of nonclassical class I MHC genes contributes to ultrasensitive chemodetection by mouse vomeronasal sensory neurons. J Neurosci 34:5121–5133
Leinders-Zufall T, Ishii T, Mombaerts P, Zufall F, Boehm T (2009) Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides. Nat Neurosci 12:1551–1558
Leypold BG, Yu CR, Leinders-Zufall T, Kim MM, Zufall F, Axel R (2002) Altered sexual and social behaviors in trp2 mutant mice. Proc Natl Acad Sci USA 99:6376–6381
Libants S, Carr K, Wu H, Teeter JH, Chung-Davidson YW, Zhang Z, Wilkerson C, Li W (2009) The sea lamprey Petromyzon marinus genome reveals the early origin of several chemosensory receptor families in the vertebrate lineage. BMC Evol Biol 9:180
Liberles SD (2014) Mammalian pheromones. Annu Rev Physiol 76:151–175
Liberles SD (2015) Trace amine-associated receptors: ligands, neural circuits, and behaviors. Curr Opin Neurobiol 34:1–7
Liberles SD, Horowitz LF, Kuang D, Contos JJ, Wilson KL, Siltberg-Liberles J, Liberles DA, Buck LB (2009) Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc Natl Acad Sci USA 106:9842–9847
Liman ER, Corey DP, Dulac C (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci USA 96:5791–5796
Loconto J, Papes F, Chang E, Stowers L, Jones EP, Takada T, Kumanovics A, Fischer Lindahl K, Dulac C (2003) Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112:607–618
Logan DW, Marton TF, Stowers L (2008) Species specificity in major urinary proteins by parallel evolution. PLoS ONE 3:e3280
Lopez F, Delgado R, Lopez R, Bacigalupo J, Restrepo D (2014) Transduction for pheromones in the main olfactory epithelium is mediated by the Ca2+-activated channel TRPM5. J Neurosci 34:3268–3278
Luo M, Fee MS, Katz LC (2003) Encoding pheromonal signals in the accessory olfactory bulb of behaving mice. Science 299:1196–1201
Luu P, Acher F, Bertrand HO, Fan J, Ngai J (2004) Molecular determinants of ligand selectivity in a vertebrate odorant receptor. J Neurosci 24:10128–10137
Ma M (2007) Encoding olfactory signals via multiple chemosensory systems. Crit Rev Biochem Mol Biol 42:463–480
Mandiyan VS, Coats JK, Shah NM (2005) Deficits in sexual and aggressive behaviors in Cnga2 mutant mice. Nat Neurosci 8:1660–1662
Marchlewska-Koj A, Cavaggioni A, Mucignat-Caretta C, Olejniczak P (2000) Stimulation of estrus in female mice by male urinary proteins. J Chem Ecol 26:2355–2366
Martinez-Marcos A (2009) On the organization of olfactory and vomeronasal cortices. Prog Neurobiol 87:21–30
Martinez-Marcos A, Halpern M (1999) Differential centrifugal afferents to the anterior and posterior accessory olfactory bulb. NeuroReport 10:2011–2015
Martini S, Silvotti L, Shirazi A, Ryba NJ, Tirindelli R (2001) Co-expression of putative pheromone receptors in the sensory neurons of the vomeronasal organ. J Neurosci 21:843–848
Matsunami H, Buck LB (1997) A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90:775–784
Matsuo T, Hattori T, Asaba A, Inoue N, Kanomata N, Kikusui T, Kobayakawa R, Kobayakawa K (2015) Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice. Proc Natl Acad Sci USA
McCarthy MM, vom Saal FS (1985) The influence of reproductive state on infanticide by wild female house mice (Mus musculus). Physiol Behav 35:843–849
Meeks JP, Arnson HA, Holy TE (2010) Representation and transformation of sensory information in the mouse accessory olfactory system. Nat Neurosci 13:723–730
Melese-d’Hospital PY, Hart BL (1985) Vomeronasal organ cannulation in male goats: evidence for transport of fluid from oral cavity to vomeronasal organ during flehmen. Physiol Behav 35:941–944
Mennella JA, Moltz H (1988) Infanticide in the male rat: the role of the vomeronasal organ. Physiol Behav 42:303–306
Meredith M (1991) Sensory processing in the main and accessory olfactory systems: comparisons and contrasts. J Steroid Biochem Mol Biol 39:601–614
Meredith M, Marques DM, O’Connell RO, Stern FL (1980) Vomeronasal pump: significance for male hamster sexual behavior. Science 207:1224–1226
Migeotte I, Communi D, Parmentier M (2006) Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses. Cytokine Growth Factor Rev 17:501–519
Mohedano-Moriano A, Pro-Sistiaga P, Ubeda-Banon I, Crespo C, Insausti R, Martinez-Marcos A (2007) Segregated pathways to the vomeronasal amygdala: differential projections from the anterior and posterior divisions of the accessory olfactory bulb. Eur J Neurosci 25:2065–2080
Mohedano-Moriano A, Pro-Sistiaga P, Ubeda-Banon I, de la Rosa-Prieto C, Saiz-Sanchez D, Martinez-Marcos A (2008) V1R and V2R segregated vomeronasal pathways to the hypothalamus. NeuroReport 19:1623–1626
Mohrhardt J, Nagel M, Fleck D, Ben-Shaul Y, Spehr M (2018) Signal detection and coding in the accessory olfactory system. Chem Senses 43:667–695
Moine F, Brechbuhl J, Nenniger Tosato M, Beaumann M, Broillet MC (2018) Alarm pheromone and kairomone detection via bitter taste receptors in the mouse Grueneberg ganglion. BMC Biol 16:12
Montague MJ, Li G, Gandolfi B, Khan R, Aken BL, Searle SM, Minx P, Hillier LW, Koboldt DC, Davis BW, Driscoll CA, Barr CS, Blackistone K, Quilez J, Lorente-Galdos B, Marques-Bonet T, Alkan C, Thomas GW, Hahn MW, Menotti-Raymond M, O’Brien SJ, Wilson RK, Lyons LA, Murphy WJ, Warren WC (2014) Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication. Proc Natl Acad Sci USA 111:17230–17235
Montani G, Tonelli S, Sanghez V, Ferrari PF, Palanza P, Zimmer A, Tirindelli R (2013) Aggressive behaviour and physiological responses to pheromones are strongly impaired in mice deficient for the olfactory G-protein-subunit G8. The Journal of physiology 591:3949–3962
Moriya-Ito K, Hayakawa T, Suzuki H, Hagino-Yamagishi K, Nikaido M (2018) Evolution of vomeronasal receptor 1 (V1R) genes in the common marmoset (Callithrix jacchus). Gene 642:343–353
Mucignat-Caretta C, Caretta A, Cavaggioni A (1995) Acceleration of puberty onset in female mice by male urinary proteins. The Journal of physiology 486:517–522
Nakamuta S, Nakamuta N, Taniguchi K, Taniguchi K (2012) Histological and ultrastructural characteristics of the primordial vomeronasal organ in lungfish. Anat Rec (Hoboken) 295:481–491
Nikaido M, Noguchi H, Nishihara H, Toyoda A, Suzuki Y, Kajitani R, Suzuki H, Okuno M, Aibara M, Ngatunga BP, Mzighani SI, Kalombo HW, Masengi KW, Tuda J, Nogami S, Maeda R, Iwata M, Abe Y, Fujimura K, Okabe M, Amano T, Maeno A, Shiroishi T, Itoh T, Sugano S, Kohara Y, Fujiyama A, Okada N (2013) Coelacanth genomes reveal signatures for evolutionary transition from water to land. Genome Res 23:1740–1748
Nodari F, Hsu FF, Fu X, Holekamp TF, Kao LF, Turk J, Holy TE (2008) Sulfated steroids as natural ligands of mouse pheromone-sensing neurons. J Neurosci 28:6407–6418
Novotny M, Harvey S, Jemiolo B, Alberts J (1985) Synthetic pheromones that promote inter-male aggression in mice. Proc Natl Acad Sci USA 82:2059–2061
Novotny M, Jemiolo B, Harvey S, Wiesler D, Marchlewska-Koj A (1986) Adrenal-mediated endogenous metabolites inhibit puberty in female mice. Science 231:722–725
Novotny MV, Jemiolo B, Wiesler D, Ma W, Harvey S, Xu F, Xie TM, Carmack M (1999) A unique urinary constituent, 6-hydroxy-6-methyl-3-heptanone, is a pheromone that accelerates puberty in female mice. Chem Biol 6:377–383
Oboti L, Perez-Gomez A, Keller M, Jacobi E, Birnbaumer L, Leinders-Zufall T, Zufall F, Chamero P (2014) A wide range of pheromone-stimulated sexual and reproductive behaviors in female mice depend on G protein G(alpha)o. BMC Biol 12:31
Ohara H, Nikaido M, Date-Ito A, Mogi K, Okamura H, Okada N, Takeuchi Y, Mori Y, Hagino-Yamagishi K (2009) Conserved repertoire of orthologous vomeronasal type 1 receptor genes in ruminant species. BMC Evol Biol 9:233
Oka Y, Saraiva LR, Korsching SI (2012) Crypt neurons express a single V1R-related ora gene. Chem Senses 37:219–227
Osakada T, Ishii KK, Mori H, Eguchi R, Ferrero DM, Yoshihara Y, Liberles SD, Miyamichi K, Touhara K (2018) Sexual rejection via a vomeronasal receptor-triggered limbic circuit. Nature communications 9:4463
Palle A, Montero M, Fernandez S, Tezanos P, de Las Heras JA, Luskey V, Birnbaumer L, Zufall F, Chamero P, Trejo JL (2020) Galphai2(+) vomeronasal neurons govern the initial outcome of an acute social competition. Scientific reports 10:894
Papes F, Logan DW, Stowers L (2010) The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell 141:692–703
Park SH, Podlaha O, Grus WE, Zhang J (2011) The microevolution of V1r vomeronasal receptor genes in mice. Genome Biol Evol 3:401–412
Peele P, Salazar I, Mimmack M, Keverne EB, Brennan PA (2003) Low molecular weight constituents of male mouse urine mediate the pregnancy block effect and convey information about the identity of the mating male. Eur J Neurosci 18:622–628
Perez-Gomez A, Bleymehl K, Stein B, Pyrski M, Birnbaumer L, Munger SD, Leinders-Zufall T, Zufall F, Chamero P (2015) Innate predator odor aversion driven by parallel olfactory subsystems that converge in the ventromedial hypothalamus. Curr Biol 25:1340–1346
Pfister P, Rodriguez I (2005) Olfactory expression of a single and highly variable V1r pheromone receptor-like gene in fish species. Proc Natl Acad Sci USA 102:5489–5494
Pin JP, Galvez T, Prezeau L (2003) Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 98:325–354
Riviere S, Challet L, Fluegge D, Spehr M, Rodriguez I (2009) Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459:574–577
Roberts SA, Davidson AJ, McLean L, Beynon RJ, Hurst JL (2012) Pheromonal induction of spatial learning in mice. Science 338:1462–1465
Roberts SA, Prescott MC, Davidson AJ, McLean L, Beynon RJ, Hurst JL (2018) Individual odour signatures that mice learn are shaped by involatile major urinary proteins (MUPs). BMC Biol 16:48
Roberts SA, Simpson DM, Armstrong SD, Davidson AJ, Robertson DH, McLean L, Beynon RJ, Hurst JL (2010) Darcin: a male pheromone that stimulates female memory and sexual attraction to an individual male’s odour. BMC Biol 8:75
Rodriguez I, Del Punta K, Rothman A, Ishii T, Mombaerts P (2002) Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors. Nat Neurosci 5:134–140
Rodriguez I, Feinstein P, Mombaerts P (1999) Variable patterns of axonal projections of sensory neurons in the mouse vomeronasal system. Cell 97:199–208
Rodriguez I, Greer CA, Mok MY, Mombaerts P (2000) A putative pheromone receptor gene expressed in human olfactory mucosa. Nat Genet 26:18–19
Rodriguez I, Mombaerts P (2002) Novel human vomeronasal receptor-like genes reveal species-specific families. Curr Biol 12:R409-411
Rubi Levy D, Sofer Y, Brumfeld V, Zilkha N, Kimchi T (2019) The nasopalatine ducts of the mouse conserve a functional role in pheromone signaling. bioRxiv 757930
Runnenburger K, Breer H, Boekhoff I (2002) Selective G protein beta gamma-subunit compositions mediate phospholipase C activation in the vomeronasal organ. Eur J Cell Biol 81:539–547
Ryba NJ, Tirindelli R (1995) A novel GTP-binding protein gamma-subunit, G gamma 8, is expressed during neurogenesis in the olfactory and vomeronasal neuroepithelia. J Biol Chem 270:6757–6767
Ryba NJ, Tirindelli R (1997) A new multigene family of putative pheromone receptors. Neuron 19:371–379
Salazar I, Brennan PA (2001) Retrograde labelling of mitral/tufted cells in the mouse accessory olfactory bulb following local injections of the lipophilic tracer DiI into the vomeronasal amygdala. Brain Res 896:198–203
Salazar I, Cifuentes JM, Sanchez-Quinteiro P (2013) Morphological and immunohistochemical features of the vomeronasal system in dogs. Anat Rec (Hoboken) 296:146–155
Salazar I, Sanchez Quinteiro P, Cifuentes JM, Garcia Caballero T (1996) The vomeronasal organ of the cat. J Anat 188:445–454
Saraiva LR, Korsching SI (2007) A novel olfactory receptor gene family in teleost fish. Genome Res 17:1448–1457
Sathyanesan A, Feijoo AA, Mehta ST, Nimarko AF, Lin W (2013) Expression profile of G-protein betagamma subunit gene transcripts in the mouse olfactory sensory epithelia. Frontiers in cellular neuroscience 7:84
Sato Y, Miyasaka N, Yoshihara Y (2005) Mutually exclusive glomerular innervation by two distinct types of olfactory sensory neurons revealed in transgenic zebrafish. J Neurosci 25:4889–4897
Schneider NY (2011) The development of the olfactory organs in newly hatched monotremes and neonate marsupials. J Anat 219:229–242
Schneider NY, Fletcher TP, Shaw G, Renfree MB (2012) Goalpha expression in the vomeronasal organ and olfactory bulb of the tammar wallaby. Chem Senses 37:567–577
Sharma K, Syed AS, Ferrando S, Mazan S, Korsching SI (2019) The chemosensory receptor repertoire of a true shark is dominated by a single olfactory receptor family. Genome Biol Evol 11:398–405
Sheehan MJ, Lee V, Corbett-Detig R, Bi K, Beynon RJ, Hurst JL, Nachman MW (2016) Selection on coding and regulatory variation maintains individuality in major urinary protein scent marks in wild mice. PLoS Genet 12:e1005891
Shi P, Zhang J (2007) Comparative genomic analysis identifies an evolutionary shift of vomeronasal receptor gene repertoires in the vertebrate transition from water to land. Genome Res 17:166–174
Shirokova E, Raguse JD, Meyerhof W, Krautwurst D (2008) The human vomeronasal type-1 receptor family–detection of volatiles and cAMP signaling in HeLa/Olf cells. FASEB J 22:1416–1425
Silva L, Antunes A (2017) Vomeronasal receptors in vertebrates and the evolution of pheromone detection. Annual review of animal biosciences 5:353–370
Silvotti L, Cavalca E, Gatti R, Percudani R, Tirindelli R (2011) A recent class of chemosensory neurons developed in mouse and rat. PLoS ONE 6:e24462
Silvotti L, Moiani A, Gatti R, Tirindelli R (2007) Combinatorial co-expression of pheromone receptors, V2Rs. J Neurochem 103:1753–1763
Smith TD, Laitman JT, Bhatnagar KP (2014) The shrinking anthropoid nose, the human vomeronasal organ, and the language of anatomical reduction. Anat Rec (Hoboken) 297:2196–2204
Speca DJ, Lin DM, Sorensen PW, Isacoff EY, Ngai J, Dittman AH (1999) Functional identification of a goldfish odorant receptor. Neuron 23:487–498
Spehr M, Kelliher KR, Li XH, Boehm T, Leinders-Zufall T, Zufall F (2006) Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J Neurosci 26:1961–1970
Stopka P, Kuntova B, Klempt P, Havrdova L, Cerna M, Stopkova R (2016) On the saliva proteome of the Eastern European house mouse (Mus musculus musculus) focusing on sexual signalling and immunity. Sci Rep 6:32481
Stowers L, Holy TE, Meister M, Dulac C, Koentges G (2002) Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295:1493–1500
Stowers L, Kuo TH (2015) Mammalian pheromones: emerging properties and mechanisms of detection. Curr Opin Neurobiol 34:103–109
Stowers L, Liberles SD (2016) State-dependent responses to sex pheromones in mouse. Curr Opin Neurobiol 38:74–79
Suarez R, Fernandez-Aburto P, Manger PR, Mpodozis J (2011) Deterioration of the Galphao vomeronasal pathway in sexually dimorphic mammals. PLoS ONE 6:e26436
Suzuki H, Nishida H, Kondo H, Yoda R, Iwata T, Nakayama K, Enomoto T, Wu J, Moriya-Ito K, Miyazaki M, Wakabayashi Y, Kishida T, Okabe M, Suzuki Y, Ito T, Hirota J, Nikaido M (2018) A single pheromone receptor gene conserved across 400 My of vertebrate evolution. Mol Biol Evol 35:2928–2939
Syed AS, Korsching SI (2014) Positive Darwinian selection in the singularly large taste receptor gene family of an “ancient” fish. Latimeria chalumnae BMC Genomics 15:650
Syed AS, Sansone A, Hassenklover T, Manzini I, Korsching SI (2017) Coordinated shift of olfactory amino acid responses and V2R expression to an amphibian water nose during metamorphosis. Cell Mol Life Sci 74:1711–1719
Syed AS, Sansone A, Nadler W, Manzini I, Korsching SI (2013) Ancestral amphibian v2rs are expressed in the main olfactory epithelium. Proc Natl Acad Sci U S A 110:7714–7719
Taha M, McMillon R, Napier A, Wekesa KS (2009) Extracts from salivary glands stimulate aggression and inositol-1, 4, 5-triphosphate (IP3) production in the vomeronasal organ of mice. Physiol Behav 98:147–155
Takami S (2002) Recent progress in the neurobiology of the vomeronasal organ. Microsc Res Tech 58:228–250
Takigami S, Mori Y, Ichikawa M (2000) Projection pattern of vomeronasal neurons to the accessory olfactory bulb in goats. Chem Senses 25:387–393
Tan S, Stowers L (2020) Bespoke behavior: mechanisms that modulate pheromone-triggered behavior. Curr Opin Neurobiol 64:143–150
Taniguchi K (2014) Phylogenic studies on the olfactory system in vertebrates. J Vet Med Sci 76:781–788
Taniguchi K, Saito S, Oikawa T (2008) Phylogenic aspects of the amphibian dual olfactory system. J Vet Med Sci 70:1–9
Thompson RN, McMillon R, Napier A, Wekesa KS (2007) Pregnancy block by MHC class I peptides is mediated via the production of inositol 1,4,5-trisphosphate in the mouse vomeronasal organ. J Exp Biol 210:1406–1412
Tirindelli R, Dibattista M, Pifferi S, Menini A (2009) From pheromones to behavior. Physiol Rev 89:921–956
Tirindelli R, Ryba NJ (1996) The G-protein gamma-subunit G gamma 8 is expressed in the developing axons of olfactory and vomeronasal neurons. Eur J Neurosci 8:2388–2398
Trouillet AC, Keller M, Weiss J, Leinders-Zufall T, Birnbaumer L, Zufall F, Chamero P (2019) Central role of G protein Galphai2 and Galphai2(+) vomeronasal neurons in balancing territorial and infant-directed aggression of male mice. Proc Natl Acad Sci USA 116:5135–5143
Tsunoda M, Miyamichi K, Eguchi R, Sakuma Y, Yoshihara Y, Kikusui T, Kuwahara M, Touhara K (2018) Identification of an intra- and inter-specific tear protein signal in rodents. Curr Biol 28:1–11
Turaga D, Holy TE (2012) Organization of vomeronasal sensory coding revealed by fast volumetric calcium imaging. J Neurosci 32:1612–1621
Venkatesh B, Lee AP, Ravi V, Maurya AK, Lian MM, Swann JB, Ohta Y, Flajnik MF, Sutoh Y, Kasahara M, Hoon S, Gangu V, Roy SW, Irimia M, Korzh V, Kondrychyn I, Lim ZW, Tay BH, Tohari S, Kong KW, Ho S, Lorente-Galdos B, Quilez J, Marques-Bonet T, Raney BJ, Ingham PW, Tay A, Hillier LW, Minx P, Boehm T, Wilson RK, Brenner S, Warren WC (2014) Elephant shark genome provides unique insights into gnathostome evolution. Nature 505:174–179
von Campenhausen H, Mori K (2000) Convergence of segregated pheromonal pathways from the accessory olfactory bulb to the cortex in the mouse. Eur J Neurosci 12:33–46
Wang G, Shi P, Zhu Z, Zhang YP (2010) More functional V1R genes occur in nest-living and nocturnal terricolous mammals. Genome Biol Evol 2:277–283
Weiss E, Kretschmer D (2018) Formyl-peptide receptors in infection, inflammation, and cancer. Trends Immunol 39:815–829
Wong WM, Cao J, Zhang X, Doyle WI, Mercado LL, Gautron L, Meeks JP (2020) Physiology-forward identification of bile acid-sensitive vomeronasal receptors. Sci Adv 6:eaaz6868
Wyatt TD (2010) Pheromones and signature mixtures: defining species-wide signals and variable cues for identity in both invertebrates and vertebrates. J Comp Physiol A 196:685–700
Wyatt TD (2017) Pheromones. Curr Biol 27:R739–R743
Yang H, Shi P (2010) Molecular and evolutionary analyses of formyl peptide receptors suggest the absence of VNO-specific FPRs in primates. J Genet Genomics 37:771–778
Yoder AD, Chan LM, Dos Reis M, Larsen PA, Campbell CR, Rasolarison R, Barrett M, Roos C, Kappeler P, Bielawski JP, Yang Z (2014) Molecular evolutionary characterization of a V1R subfamily unique to Strepsirrhine primates. Genome Biol Evol 6:213–227
Yoder AD, Larsen PA (2014) The molecular evolutionary dynamics of the vomeronasal receptor (class 1) genes in primates: a gene family on the verge of a functional breakdown. Front Neuroanat 8:153
Yohe LR, Davies KTJ, Rossiter SJ, Davalos LM (2019) Expressed vomeronasal type-1 receptors (V1rs) in bats uncover conserved sequences underlying social chemical signaling. Genome Biol Evol 11:2741–2749
Yoon H, Enquist LW, Dulac C (2005) Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell 123:669–682
Yoshihara Y, Kawasaki M, Tamada A, Fujita H, Hayashi H, Kagamiyama H, Mori K (1997) OCAM: a new member of the neural cell adhesion molecule family related to zone-to-zone projection of olfactory and vomeronasal axons. J Neurosci 17:5830–5842
Young JM, Kambere M, Trask BJ, Lane RP (2005) Divergent V1R repertoires in five species: amplification in rodents, decimation in primates, and a surprisingly small repertoire in dogs. Genome Res 15:231–240
Young JM, Massa HF, Hsu L, Trask BJ (2010) Extreme variability among mammalian V1R gene families. Genome Res 20:10–18
Young JM, Trask BJ (2007) V2R gene families degenerated in primates, dog and cow, but expanded in opossum. Trends Genet 23:212–215
Zancanaro C, Caretta CM, Bolner A, Sbarbati A, Nordera GP, Osculati F (1997) Biogenic amines in the vomeronasal organ. Chem Senses 22:439–445
Zapilko V, Korsching SI (2016) Tetrapod V1R-like ora genes in an early-diverging ray-finned fish species: the canonical six ora gene repertoire of teleost fish resulted from gene loss in a larger ancestral repertoire. BMC Genomics 17:83
Zhang J, Webb DM (2003) Evolutionary deterioration of the vomeronasal pheromone transduction pathway in catarrhine primates. Proc Natl Acad Sci U S A 100:8337–8341
Zhang X, Rodriguez I, Mombaerts P, Firestein S (2004) Odorant and vomeronasal receptor genes in two mouse genome assemblies. Genomics 83:802–811
Zhang Z, Nikaido M (2020) Inactivation of ancV1R as a predictive signature for the loss of vomeronasal system in mammals. Genome Biol Evol 12:766–778
Zhao H, Xu D, Zhang S, Zhang J (2011) Widespread losses of vomeronasal signal transduction in bats. Mol Biol Evol 28:7–12
Zufall F, Leinders-Zufall T (2007) Mammalian pheromone sensing. Curr Opin Neurobiol 17:483–489
Acknowledgments
I am grateful to Anna Tirindelli for supporting the graphical part of this work and to Maria Tirindelli for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares that he has no conflict of interest.
Ethical approval
This review does not contain any previously unpublished studies with human participants or animals.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tirindelli, R. Coding of pheromones by vomeronasal receptors. Cell Tissue Res 383, 367–386 (2021). https://doi.org/10.1007/s00441-020-03376-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-020-03376-6