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1.  Synchronous evolution of an odor biosynthesis pathway and behavioral response 
Current biology : CB  2012;23(1):11-20.
SUMMARY
Background
Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown.
Results
Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout.
Conclusions
TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.
doi:10.1016/j.cub.2012.10.047
PMCID: PMC3543494  PMID: 23177478
2.  Learned recognition of maternal signature odors mediates the first suckling episode in mice 
Current biology : CB  2012;22(21):1998-2007.
Summary
Background
Soon after birth all mammals must initiate milk suckling to survive. In rodents, this innate behavior is critically dependent on uncharacterized maternally-derived chemosensory ligands. Recently the first pheromone sufficient to initiate suckling was isolated from the rabbit. Identification of the olfactory cues that trigger first suckling in the mouse would provide the means to determine the neural mechanisms that generate innate behavior.
Results
Here we use behavioral analysis, metabolomics, and calcium imaging of primary sensory neurons and find no evidence of ligands with intrinsic bioactivity, such as pheromones, acting to promote first suckling in the mouse. Instead, we find that the initiation of suckling is dependent on variable blends of maternal ‘signature odors’ that are learned and recognized prior to first suckling.
Conclusions
As observed with pheromone-mediated behavior, the response to signature odors releases innate behavior. However, this mechanism tolerates variability in both the signaling ligands and sensory neurons which may maximize the probability that this first essential behavior is successfully initiated. These results suggest that mammalian species have evolved multiple strategies to ensure the onset of this critical behavior.
doi:10.1016/j.cub.2012.08.041
PMCID: PMC3494771  PMID: 23041191
3.  Sexual dimorphism in olfactory signaling 
Current opinion in neurobiology  2010;20(6):770-775.
What makes males and females behave differently? While genetic master-regulators commonly underlie physical differences, sexually dimorphic behavior is additionally influenced by sensory input such as olfactory cues. Olfaction requires both ligands for signaling and sensory neural circuits for detection. Specialized subsets of each interact to generate gender-dimorphic behavior. It has long been accepted that males and females emit sex-specific odor compounds that function as pheromones to promote stereotypic behavior. Significant advances have now been made in purifying and isolating several of these sex-specific olfactory ligands. In contrast, the neural mechanisms that enable a gender dimorphic response to these odors remain largely unknown. However, first progress has been made in identifying components of sexually dimorphic olfactory circuits in both Drosophila and the mouse.
doi:10.1016/j.conb.2010.08.015
PMCID: PMC3005963  PMID: 20833534
4.  Olfactory mechanisms of stereotyped behavior: on the scent of specialized circuits 
Current opinion in neurobiology  2010;20(3):274-280.
Summary
Investigation of how specialized olfactory cues, such as pheromones, are detected has primarily focused on the function of receptor neurons within a subsystem of the nasal cavity, the vomeronasal organ (VNO). Behavioral analyses have long indicated that additional, non-VNO olfactory neurons are similarly necessary for pheromone detection; however the identity of these neurons has been a mystery. Recent molecular, behavioral, and genomic approaches have led to the identification of multiple atypical sensory circuits that display characteristics suggestive of a specialized function. This review focuses on these non-VNO receptors and neurons, and evaluates their potential for mediating stereotyped olfactory behavior in mammals.
doi:10.1016/j.conb.2010.02.013
PMCID: PMC2883022  PMID: 20338743
5.  The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs 
Cell  2010;141(4):692-703.
Summary
Potential predators emit uncharacterized chemosignals that warn receiving species of danger. Neurons that sense these stimuli remain unknown. Here we show that detection and processing of fear-evoking odors emitted from cat, rat, and snake require the function of sensory neurons in the vomeronasal organ. To investigate the molecular nature of the sensory cues emitted by predators, we isolated the salient ligands from two species using a combination of innate behavioral assays in naïve receiving animals, calcium imaging, and cFos induction. Surprisingly, the defensive behavior-promoting activity released by other animals is encoded by species-specific ligands belonging to the major urinary protein (Mup) family, homologs of aggression-promoting mouse pheromones. We show that recombinant Mup proteins are sufficient to activate sensory neurons and initiate defensive behavior similar to native odors. This co-option of existing sensory mechanisms provides a molecular solution to the difficult problem of evolving a variety of species-specific molecular detectors.
doi:10.1016/j.cell.2010.03.037
PMCID: PMC2873972  PMID: 20478258
6.  Analysis of Male Pheromones That Accelerate Female Reproductive Organ Development 
PLoS ONE  2011;6(2):e16660.
Male odors can influence a female's reproductive physiology. In the mouse, the odor of male urine results in an early onset of female puberty. Several volatile and protein pheromones have previously been reported to each account for this bioactivity. Here we bioassay inbred BALB/cJ females to study pheromone-accelerated uterine growth, a developmental hallmark of puberty. We evaluate the response of wild-type and mutant mice lacking a specialized sensory transduction channel, TrpC2, and find TrpC2 function to be necessary for pheromone-mediated uterine growth. We analyze the relative effectiveness of pheromones previously identified to accelerate puberty through direct bioassay and find none to significantly accelerate uterine growth in BALB/cJ females. Complementary to this analysis, we have devised a strategy of partial purification of the uterine growth bioactivity from male urine and applied it to purify bioactivity from three different laboratory strains. The biochemical characteristics of the active fraction of all three strains are inconsistent with that of previously known pheromones. When directly analyzed, we are unable to detect previously known pheromones in urine fractions that generate uterine growth. Our analysis indicates that pheromones emitted by males to advance female puberty remain to be identified.
doi:10.1371/journal.pone.0016660
PMCID: PMC3035649  PMID: 21347429
8.  Species Specificity in Major Urinary Proteins by Parallel Evolution 
PLoS ONE  2008;3(9):e3280.
Species-specific chemosignals, pheromones, regulate social behaviors such as aggression, mating, pup-suckling, territory establishment, and dominance. The identity of these cues remains mostly undetermined and few mammalian pheromones have been identified. Genetically-encoded pheromones are expected to exhibit several different mechanisms for coding 1) diversity, to enable the signaling of multiple behaviors, 2) dynamic regulation, to indicate age and dominance, and 3) species-specificity. Recently, the major urinary proteins (Mups) have been shown to function themselves as genetically-encoded pheromones to regulate species-specific behavior. Mups are multiple highly related proteins expressed in combinatorial patterns that differ between individuals, gender, and age; which are sufficient to fulfill the first two criteria. We have now characterized and fully annotated the mouse Mup gene content in detail. This has enabled us to further analyze the extent of Mup coding diversity and determine their potential to encode species-specific cues.
Our results show that the mouse Mup gene cluster is composed of two subgroups: an older, more divergent class of genes and pseudogenes, and a second class with high sequence identity formed by recent sequential duplications of a single gene/pseudogene pair. Previous work suggests that truncated Mup pseudogenes may encode a family of functional hexapeptides with the potential for pheromone activity. Sequence comparison, however, reveals that they have limited coding potential. Similar analyses of nine other completed genomes find Mup gene expansions in divergent lineages, including those of rat, horse and grey mouse lemur, occurring independently from a single ancestral Mup present in other placental mammals. Our findings illustrate that increasing genomic complexity of the Mup gene family is not evolutionarily isolated, but is instead a recurring mechanism of generating coding diversity consistent with a species-specific function in mammals.
doi:10.1371/journal.pone.0003280
PMCID: PMC2533699  PMID: 18815613

Results 1-8 (8)