Multiple New and Isolated Families Within the Mouse Superfamily of V1r Vomeronasal Receptors

Nature Neuroscience. Feb, 2002  |  Pubmed ID: 11802169

Seven-transmembrane-domain proteins encoded by the vomeronasal receptor V1r and V2r gene superfamilies, and expressed by vomeronasal sensory neurons, are believed to be pheromone receptors in rodents. Four V1r gene families have been described in the mouse (V1ra, V1rb, V1rc and V3r). Here we have screened near-complete mouse genomic databases to obtain a first global draft of the mouse V1r repertoire, including 104 new V1r genes. It comprises eight new and extremely isolated families in addition to the four families previously identified. Members of these new families were expressed in vomeronasal sensory neurons. The genome-wide view revealed great sequence diversity within the V1r superfamily. Phylogenetic analyses suggested an ancient original radiation, followed by the isolation, divergence and expansion of families by extensive gene duplications and frequent gene loss. The isolated nature of these gene families probably reflects a specialization of different receptor classes in the detection of specific types of chemicals.

Aberrant Sensory Innervation of the Olfactory Bulb in Neuropilin-2 Mutant Mice

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. May, 2002  |  Pubmed ID: 12019322

The mammalian olfactory system consists of two anatomically segregated structures, the main olfactory system and the vomeronasal system, which each detect distinct types of chemical stimuli in the environment. During development, sensory neurons establish precise axonal connections with their respective targets within the olfactory bulb. The specificity of the odorant or vomeronasal receptor expressed by the sensory neuron is crucial in this process, yet it is less clear which of the more conventional axon guidance molecules are involved. Here, we show that neuropilin-2, a coreceptor for some of the class 3 semaphorins, is expressed in subpopulations of olfactory and vomeronasal sensory neurons. We generated a knock-out mutation in the neuropilin-2 gene by gene targeting in embryonic stem cells. Neuropilin-2 mutant mice exhibit profound and distinct effects on target innervation within the olfactory bulb. In the main olfactory system, axons of olfactory sensory neurons penetrate into the deeper layers of the main olfactory bulb. In the vomeronasal system, axonal fasciculation within the vomeronasal nerve is affected; some axons are misrouted and innervate glomeruli in an ectopic domain of the accessory olfactory bulb.

Novel Human Vomeronasal Receptor-like Genes Reveal Species-specific Families

Current Biology : CB. Jun, 2002  |  Pubmed ID: 12123587

Deficient Pheromone Responses in Mice Lacking a Cluster of Vomeronasal Receptor Genes

Nature. Sep, 2002  |  Pubmed ID: 12214233

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.

A Divergent Pattern of Sensory Axonal Projections is Rendered Convergent by Second-order Neurons in the Accessory Olfactory Bulb

Neuron. Sep, 2002  |  Pubmed ID: 12354396

The mammalian vomeronasal system is specialized in pheromone detection. The neural circuitry of the accessory olfactory bulb (AOB) provides an anatomical substrate for the coding of pheromone information. Here, we describe the axonal projection pattern of vomeronasal sensory neurons to the AOB and the dendritic connectivity pattern of second-order neurons. Genetically traced sensory neurons expressing a given gene of the V2R class of vomeronasal receptors project their axons to six to ten glomeruli distributed in globally conserved areas of the AOB, a theme similar to V1R-expressing neurons. Surprisingly, second-order neurons tend to project their dendrites to glomeruli innervated by axons of sensory neurons expressing the same V1R or the same V2R gene. Convergence of receptor type information in the olfactory bulb may represent a common design in olfactory systems.

Pheromone Detection Mediated by a V1r Vomeronasal Receptor

Nature Neuroscience. Dec, 2002  |  Pubmed ID: 12436115

Nosing into Pheromone Detectors

Nature Neuroscience. May, 2003  |  Pubmed ID: 12715007

Synthesis of Mono- and Bisdihydrodipyridopyrazines and Assessment of Their DNA Binding and Cytotoxic Properties

Journal of Medicinal Chemistry. Feb, 2004  |  Pubmed ID: 14761199

Aminoalkyl-substituted monomeric and dimeric dihydrodipyridopyrazines have been synthesized and evaluated as antitumor agents. Potent cytotoxic compounds were identified in both series. Biochemical and biophysical studies indicated that all these compounds strongly stabilized the duplex structure of DNA and some of them elicited a selectivity for GC-rich sequences. Sequence recognition by of the dimeric dihydrodipyridopyrazines is reminiscent of that of certain antitumor bisnaphthalimides. Compared to monomers, corresponding dimeric derivatives showed higher affinity for DNA. This property was attributed to a bisintercalative binding to DNA. This assumption was indirectly probed by electric linear dichroism and DNA relaxation experiments. DNA provides a bioreceptor for these dihydrodipyridopyrazine derivatives, but no poisoning of human topoisomerases I or II was detected. Most of the compounds efficiently inhibited the growth of L1210 murine leukemia cells and perturbed the cell cycle progression (with a G2/M block in most cases). A weak but noticeable in vivo antitumor activity was observed with one of the dimeric compounds. This studies identifies monomeric and dimeric dihydrodipyridopyrazines as a new class of DNA-targeted antitumor agents.

Odorant and Vomeronasal Receptor Genes in Two Mouse Genome Assemblies

Genomics. May, 2004  |  Pubmed ID: 15081110

Odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) are large superfamilies of chemosensory receptors. As an extension of previous research using the 2001 Celera mouse genome assembly, we analyzed OR and V1R genes in the 2002 public mouse genome assembly. We identified 1403 OR genes (1068 potentially intact) and 332 V1R genes (164 potentially intact) in this C57BL/6J mouse genome. This expands the mouse OR and V1R superfamilies by adding approximately 100 OR and approximately 40 V1R potentially intact genes. The description of the genomic distribution of OR genes is more complete and accurate, and two major errors in OR gene distribution in the 2001 Celera assembly were corrected. For the first time, the complete genomic distribution of V1R genes was investigated in detail and placed in context with that of OR genes. V1R genes, like OR genes, tend to form clusters of similar genes in the genome. Comparison between the two genome assemblies revealed a high rate of single-nucleotide polymorphisms (SNPs) in both OR and V1R genes. The high ratio of nonsynonymous SNPs over synonymous SNPs in V1R genes suggests positive selection for these genes, possibly favoring species-specific and strain-specific pheromone detection. In addition, detailed analysis of the SNP rate aided in the identification of key residues in ORs.

Axon Guidance of Mouse Olfactory Sensory Neurons by Odorant Receptors and the Beta2 Adrenergic Receptor

Cell. Jun, 2004  |  Pubmed ID: 15186782

Odorant receptors (ORs) provide the core determinant of identity for axons of olfactory sensory neurons (OSNs) to coalesce into glomeruli in the olfactory bulb. Here, using gene targeting in mice, we examine how the OR protein determines axonal identity. An OR::GFP fusion protein is present in axons, consistent with a direct function of ORs in axon guidance. When the OR coding region is deleted, we observe OSNs that coexpress other ORs that function in odorant reception and axonal identity. It remains unclear if such coexpression is normally prevented by negative feedback on OR gene choice. A drastic reduction in OR protein level produces axonal coalescence into novel, remote glomeruli. By contrast, chimeric ORs and ORs with minor mutations perturb axon outgrowth. Strikingly, the beta2 adrenergic receptor can substitute for an OR in glomerular formation when expressed from an OR locus. Thus, ORs have not evolved a unique function in axon guidance.

Pheromone Receptors in Mammals

Hormones and Behavior. Sep, 2004  |  Pubmed ID: 15325223

In most mammals, pheromone perception mediates intraspecies interactions related to reproduction, such as mate recognition, intermale aggressive behaviors, or exchanges between females and their offspring. Recent molecular findings, particularly the identification of two large pheromone receptor gene superfamilies, provide today invaluable tools to better understand the way mammals make sense of pheromonal information.

Olfactory Expression of a Single and Highly Variable V1r Pheromone Receptor-like Gene in Fish Species

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2005  |  Pubmed ID: 15809442

Sensory neurons expressing members of the seven-transmembrane V1r receptor superfamily allow mice to perceive pheromones. These receptors, which exhibit no sequence homology to any known protein except a weak similarity to taste receptors, have only been found in mammals. In the mouse, the V1r repertoire contains >150 members, which are expressed by neurons of the vomeronasal organ, a structure present exclusively in some tetrapod species. Here, we report the existence of a single V1r gene in multiple species of a non-terrestrial, vomeronasal organ-lacking taxon, the teleosts. In zebrafish, this V1r gene is expressed in chemosensory neurons of the olfactory rosette with a punctate distribution, strongly suggesting a role in chemodetection. This unique receptor gene exhibits a remarkably high degree of sequence variability between fish species. It likely corresponds to the original V1r present in the common ancestor of vertebrates, which led to the large and very diverse expansion of vertebrate pheromone receptor repertoires, and suggests the presence of V1rs in multiple nonmammalian phyla.

Remarkable Diversity of Mammalian Pheromone Receptor Repertoires

Proceedings of the National Academy of Sciences of the United States of America. May, 2005  |  Pubmed ID: 15870190

Zebrafish (Danio Rerio) As a Model for the Study of Vaccination Against Viral Haemorrhagic Septicemia Virus (VHSV)

Vaccine. Jul, 2006  |  Pubmed ID: 16777275

The rhabdovirus viral haemorrhagic septicemia virus (VHSV) is the etiological agent of one of the most important salmonid viral diseases. In the present work, the ability of VHSV to infect and replicate in zebrafish at low temperature (15 degrees C) was demonstrated. Zebrafish was also used to determine the effectiveness of the recombinant virus rIHNV-Gvhsv GFP as a live attenuated vaccine against the virulent VHSV strain. Fish intraperitoneally injected with 3 x 10(6) to 3 x 10(5)TCID50/ml of the wild type VHSV showed a 100% of cumulative mortality, meanwhile only 57% of mortality was obtained in bath infections. Infected fish showed external clinical signs and histological observations revealed the appearance of small haemorrhages in the muscle, kidney, liver and dermis. Neither mortalities nor clinical signs were recorded in fish infected with a live attenuated recombinant virus. By RT-PCR technique, VHSV was detected in all the organs as early as 24h, but the recombinant virus was not detected in all the sampled days. VHSV was able to replicate "in vitro" in head kidney cells but the replication capacity of the attenuated viral strain was limited. The recombinant virus rIHNV-Gvhsv GFP was able to protect against VHSV with a survival rate ranging from 20% to 60% depending of the vaccine dose. The increase of TLR3, IFNalphabeta, Mx, IFNgamma and TNFalpha expression at 72h post-infection in the kidney of VHSV-infected fish contrasted with the results obtained with the avirulent virus, which did not induce an increment of this expression in infected fish. Zebrafish is a suitable animal model to study VHSV infection and immune (innate and adaptive) responses and, more importantly, we demonstrate for the first time the usefulness of the zebrafish as a vaccination model to viral diseases. In addition, the high protection obtained with the live attenuated virus demonstrates that the zebrafish is able to mount an efficient antiviral immune response at 15 degrees C.

Projection of the Grüneberg Ganglion to the Mouse Olfactory Bulb

The European Journal of Neuroscience. Jun, 2006  |  Pubmed ID: 16819977

In mammals, sensory neurons from the main olfactory and vomeronasal systems project their axons to the olfactory bulbs in the brain. We here report that a cluster of neurons, distinct from these two systems, located at the very tip of the mouse nose and called the Grüneberg ganglion expresses the mature olfactory-sensory neuron-specific marker olfactory marker protein (OMP), but is unlikely to express known odorant or pheromone receptors. The ganglion is present at birth and maintained during adult life. Tracing experiments indicate that these neurons target ipsilaterally to a specific set of glomeruli located on the caudal part of the olfactory bulb, and that this connection is necessary for the survival of the ganglion. The glomerular targets are structures previously proposed to be associated with suckling behaviour. These observations strongly suggest that this peculiar olfactory neuronal population plays a sensory role, possibly linked to chemoperception.

Divergent Evolution Among Teleost V1r Receptor Genes

PloS One. 2007  |  Pubmed ID: 17440615

The survival of vertebrate species is dependent on the ability of individuals to adequately interact with each other, a function often mediated by the olfactory system. Diverse olfactory receptor repertoires are used by this system to recognize chemicals. Among these receptors, the V1rs, encoded by a very large gene family in most mammals, are able to detect pheromones. Teleosts, which also express V1r receptors, possess a very limited V1r repertoire. Here, taking advantage of the possibility to unequivocally identify V1r orthologs in teleosts, we analyzed the olfactory expression and evolutionary constraints of a pair of clustered fish V1r receptor genes, V1r1 and V1r2. Orthologs of the two genes were found in zebrafish, medaka, and threespine stickleback, but a single representative was observed in tetraodontidae species. Analysis of V1r1 and V1r2 sequences from 12 different euteleost species indicate different evolutionary rates between the two paralogous genes, leading to a highly conserved V1r2 gene and a V1r1 gene under more relaxed selective constraint. Moreover, positively-selected sites were detected in specific branches of the V1r1 clade. Our results suggest a conserved agonist specificity of the V1R2 receptor between euteleost species, its loss in the tetraodontidae lineage, and the acquisition of different chemosensory characteristics for the V1R1 receptor.

Adenylyl Cyclase-dependent Axonal Targeting in the Olfactory System

Development (Cambridge, England). Jul, 2007  |  Pubmed ID: 17537788

The vertebrate olfactory bulb is a remarkably organized neuronal structure, in which hundreds of functionally different sensory inputs are organized into a highly stereotyped topographical map. How this wiring is achieved is not yet understood. Here, we show that the olfactory bulb topographical map is modified in adenylyl cyclase 3 (adenylate cyclase 3)-deficient mice. In these mutants, axonal projection targets corresponding to specific odorant receptors are disorganized, are no longer exclusively innervated by functionally identical axonal projections and shift dramatically along the anteroposterior axis of the olfactory bulb. Moreover, the cyclase depletion leads to the prevention of neuropilin 1 (Nrp1) expression in olfactory sensory neuron axonal projections. Taken together, our data point to a major role played by a crucial element of the odorant-induced transduction cascade, adenylyl cyclase 3, in the targeting of olfactory sensory neuron axons towards the brain. This mechanism probably involves the regulation of receptor genes known to be crucial in axonal guidance processes.

Gene Cluster Lock After Pheromone Receptor Gene Choice

The EMBO Journal. Jul, 2007  |  Pubmed ID: 17611603

In mammals, perception of pheromones is based on the expression in each vomeronasal sensory neuron of a limited set of receptor genes, chosen among a large repertoire. Here, we report an extremely tight control of the monogenic and monoallelic transcription of the V1rb2 receptor gene. Combining genetic and electrophysiological approaches, we show that the transcription of a non-functional V1r allele leads to the coexpression of another, functional V1r gene. The choice of this coexpressed gene surprisingly includes genes located on the cluster homologous to the one from which the mutant allele is transcribed. However, V1r genes located in cis relative to the transcribed mutant allele are excluded from the coexpression choice. Our observations strongly suggest a monogenic regulatory mechanism acting (a) at a general level, via the expression of the V1r receptor itself, and (b) at a more local level, defined by the V1r gene cluster.

Odorant and Pheromone Receptor Gene Regulation in Vertebrates

Current Opinion in Genetics & Development. Oct, 2007  |  Pubmed ID: 17709237

The largest mammalian gene family codes for odorant receptors and is exclusively devoted to the perception of the outside world. Its expression is very peculiar, since olfactory sensory neurons are only allowed to express a single of its numerous members, from a single parental allele. How this is achieved is unknown, but recent work points to multiple regulatory mechanisms, possibly shared by pheromone receptor genes, acting at (a) a general level, via the expression of the chemoreceptor itself and (b) a more restricted level, defined by activator elements.

A Common Gene Exclusion Mechanism Used by Two Chemosensory Systems

The European Journal of Neuroscience. Feb, 2009  |  Pubmed ID: 19200072

Sensory coding strategies within vertebrates involve the expression of a limited number of receptor types per sensory cell. In mice, each vomeronasal sensory neuron transcribes monoallelically a single V1R pheromone receptor gene, chosen from a large V1R repertoire. The nature of the signals leading to this strict receptor expression is unknown, but is apparently based on a negative feedback mechanism initiated by the transcription of the first randomly chosen functional V1R gene. We show, in vivo, that the genetic replacement of the V1rb2 pheromone receptor coding sequence by an unrelated one from the odorant receptor gene M71 maintains gene exclusion. The expression of this exogenous odorant receptor in vomeronasal neurons does not trigger the transcription of odorant receptor-associated signalling molecules. These results strongly suggest that despite the different odorant and vomeronasal receptor expression sites, function and transduction cascades, a common mechanism is used by these chemoreceptors to regulate their transcription.

Beta-Glucan Administration Enhances Disease Resistance and Some Innate Immune Responses in Zebrafish (Danio Rerio)

Fish & Shellfish Immunology. Aug, 2009  |  Pubmed ID: 19232393

The present study was conducted to investigate the effect of beta-glucan (derived from Saccharomyces cerevisiae) on the immune response and its protection against an infection of the bacterial pathogen Aeromonas hydrophila in zebrafish (Danio rerio). Zebrafish received beta-glucan by intraperitoneal injection at three different concentrations (5, 2 and 0.5 mgml(-1)) at 6, 4 and 2 days prior the challenge. On challenge day the control and beta-glucan pretreated zebrafish were intraperitoneally injected with A. hydrophila and mortality was recorded for 4 days. Intraperitoneal injection of 5 mgml(-1) of beta-glucan significantly reduced the mortality. A single injection of 5 mgml(-1) of beta-glucan 6 days before challenge also enhanced significantly the survival against the infection. The treatment with beta-glucan increased the myelomonocytic cell population in the kidney at 6h postchallenge with A. hydrophila. Moreover it enhanced the ability of kidney cells to kill A. hydrophila. beta-glucan did not affect the expression of TNFalpha or IL-1 beta but seemed to modulate IFNgamma and chemokine expression in kidney.

Formyl Peptide Receptor-like Proteins Are a Novel Family of Vomeronasal Chemosensors

Nature. May, 2009  |  Pubmed ID: 19387439

Mammals rely heavily on olfaction to interact adequately with each other and with their environment. They make use of seven-transmembrane G-protein-coupled receptors to identify odorants and pheromones. These receptors are present on dendrites of olfactory sensory neurons located in the main olfactory or vomeronasal sensory epithelia, and pertain to the odorant, trace amine-associated receptor and vomeronasal type 1 (ref. 4) or 2 (refs 5-7) receptor superfamilies. Whether these four sensor classes represent the complete olfactory molecular repertoire used by mammals to make sense of the outside world is unknown. Here we report the expression of formyl peptide receptor-related genes by vomeronasal sensory neurons, in multiple mammalian species. Similar to the four known olfactory receptor gene classes, these genes encode seven-transmembrane proteins, and are characterized by monogenic transcription and a punctate expression pattern in the sensory neuroepithelium. In vitro expression of mouse formyl peptide receptor-like 1, 3, 4, 6 and 7 provides sensitivity to disease/inflammation-related ligands. Establishing an in situ approach that combines whole-mount vomeronasal preparations with dendritic calcium imaging in the intact neuroepithelium, we show neuronal responses to the same molecules, which therefore represent a new class of vomeronasal agonists. Taken together, these results suggest that formyl peptide receptor-like proteins have an olfactory function associated with the identification of pathogens, or of pathogenic states.

[Prevalence, Clinical-endoscopic Characteristics and Predictive Factors of Barrett's Esophagus in Endoscopic Screening for Gastric Cancer]

Revista De Gastroenterología Del Perú : órgano Oficial De La Sociedad De Gastroenterología Del Perú. Jan-Mar, 2009  |  Pubmed ID: 19424405

Determine the prevalence, clinical-epidemiological characteristics and predictive factors for Barrets Esophagus (BE).

[Preneoplastic Gastric Lesions and Helicobacter Pylori in Endoscopic Detection and Early Diagnosis of Gastric Cancer in a Population of a Medium and High Socio-economic Level]

Revista De Gastroenterología Del Perú : órgano Oficial De La Sociedad De Gastroenterología Del Perú. Jul-Sep, 2009  |  Pubmed ID: 19898593

To determine the prevalence and characteristics of premalignant gastric lesions and its relationship with helicobacter pylori infection.

The Chemical MUPpeteer

Cell. May, 2010  |  Pubmed ID: 20478249

Rodents exhibit an innate fear-like behavior when they sense the chemical traces of predators. In this issue, Papes et al. (2010) report that the major urinary proteins (Mups) released by predators are detected by sensory neurons in the mouse vomeronasal organ (which also detects pheromones involved in aggression), triggering a fear response.

Water Quality of a Port in NW Mexico and Its Rehabilitation with Swell Energy

Marine Pollution Bulletin. Jan, 2010  |  Pubmed ID: 19783258

Ensenada Harbor is one of the most important ports of Mexico. Anthropogenic activities have affected the area over several decades, leading to the accumulation of contaminants in its sediments, which eventually are re-suspended into the water column. In spite of water treatment of the tributaries that discharge into the Ensenada Harbor, the water circulation patterns of the harbor, which consist of closed eddies in the northern and southeastern sector, favor the accumulation of those contaminants and hinder exchange with adjacent seawater. Samples collected in October of 2005 registered 63 microM total inorganic nitrogen and 280 mg/L of COD, confirming that this is a highly contaminated environment when compared with other water bodies of North America. Such concentrations can be lowered up to 80% by using a wave energy pumping system that demonstrates the possibility to gradually dilute these contaminants and rehabilitate the Ensenada Harbor.

[International Reference Prices and Cost Minimization Analysis for the Regulation of Medicine Prices in Colombia]

Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research. Jul-Aug, 2011  |  Pubmed ID: 21839891

OBJETIVES: To suggest a scheme of decision making on pricing for medicines that are part of Free Regulated Regime, a regulation way of the pharmaceutical pricing policy in Colombia. It includes two regulation tools: international reference prices and a cost minimization analysis methodology.

Anti-CENPI Autoantibodies in Scleroderma Patients with Features of Autoimmune Liver Diseases

Clinica Chimica Acta; International Journal of Clinical Chemistry. Nov, 2011  |  Pubmed ID: 21888900

Anticentromere autoantibodies have been reported to be associated with scleroderma and serve as a marker in different rheumatic diseases in humans. Major centromere autoantigens described so far include constitutive kinetochore proteins such as CENPA, CENPB, CENPC and CENPH and facultative proteins such as CENPE, CENPF and INCENP. We examined the inner kinetochore component CENPI as a new putative centromere autoantigen in scleroderma patients.

Penile Metastasis of Prostatic Adenocarcinoma. Case Report

Archivos Españoles De Urología. Dec, 2011  |  Pubmed ID: 22228897

Penile metastases are late manifestations of a primary tumor, and they are a sign of poor prognosis. We report a case of a rare presentation: penile metastases from prostate cancer.