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Olfaction
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Olfaction
Olfaction I Mori Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0924
Olfaction is a major sense in animals. The detection of volatile chemical compounds is an important attribute for any animal to survive and reproduce in the natural environment. Different animals utilize different types of olfactory organs. For example, humans detect odors through the olfactory epithelium of the nose, whereas most insects detect odors through their antennae. Although olfactory systems are divergent throughout evolution, olfactory receptor neurons possess common properties and structure. It is intriguing to realize that even fish have an olfactory organ that is distinct in function and structure from its gustatory organ, but is similar to the olfactory organ of mammals. Similarly, molecular analysis of olfaction reveals that on sensing olfactory stimuli, essentially the same signaling events occur in vertebrates as in invertebrate species. In this review, the mammalian olfactory system is described as an example of vertebrate olfactory systems. This review also briefly considers the olfactory system of the nematode Caenorhabditis elegans, which is one of the bestcharacterized sensory systems in invertebrates at molecular and cellular levels.
Olfaction in Mammals The mammalian olfactory system is one of the most evolved sensory systems. Even humans have the ability to detect and discriminate at least 10 000 different odorants. In mammals, odors are sensed in the olfactory epithelium of the nasal cavity, where olfactory neurons are distributed in such a way that the sensory cilia of each olfactory neuron face the nasal cavity. Olfaction first occurs in the sensory cilia of olfactory neurons, and the generated olfactory signals are transmitted to the olfactory cortex and to other area of the brain through synaptic connections of olfactory neurons with downstream neurons, such as mitral or tufted cells, in the main olfactory bulb. In most cases, mammals have a second olfactory organ called the vomeronasal organ (VNO), which is situated on the lower side of the nasal cavity. The VNO detects pheromones and is particularly important for some animals such as mice, in which pheromones play a key role in controlling their behaviors. Olfactory sensation in the VNO is transmitted to the accessory olfactory bulb, which occupies a distinct area of the main olfactory bulb. Since the areas of brain
that receive signals from the accessory olfactory bulb are different from those that receive signals from the main olfactory bulb, the effects of odorant sensation and pheromone sensation cause different behavioral and emotional outcomes.
Olfactory Receptors It is understood that all olfactory receptors are found to be G-protein-coupled seven-transmembrane domain receptors and are usually encoded by the largest gene family in any animal. In mammals, there are about 1000 genes that encode olfactory receptors in the olfactory epithelium. In the VNO, there are two olfactory receptor families: the V1R family, which consists of 35 members; and the V2R family, which consists of 150 members. These two receptor families are likely to detect pheromones. The members of olfactory receptor families are very diverse in their amino acid sequences, which is consistent with the fact that animals detect a large number of odorants. Perhaps, each odorant interacts with and activates a single or small subset of olfactory receptor proteins.
Organization of Olfactory Receptors There are a number of interesting questions regarding organization of olfactory receptors. First, molecular and cellular studies indicate that each olfactory neuron seems to express only a single type of olfactory receptor. How a single gene is chosen from among 1000 olfactory receptor-coding genes in a particular olfactory neuron remains a mystery. Second, recent analysis has revealed spatially distinct expression of genes encoding olfactory receptors in the olfactory epithelium. Although these receptors are diverse in their makeup, they are categorized on the basis of the zone in which they are expressed. There are four zones and each olfactory receptor is expressed in one of these zones. The function of the zonal organization is unknown. In the VNO, there appear to be two zones: one that expresses members of the V1R family, and the other that expresses members of the V2R family. On the surface of the main olfactory bulb, there are about 2000 units of structures called glomeruli, where axons of olfactory neurons synapse onto downstream neurons, such as mitral cells. Interestingly, each olfactory neuron projects its axon toward a specific glomerulus. Furthermore, olfactory neurons that express the same type of olfactory receptors send their axons to the same glomerulus. How is this precise olfactory projection established? In one model, the olfactory receptor per se is thought to be a determinant for projection to a particular glomerulus, since messages (mRNAs) for olfactory receptors have been unexpectedly detected in
Olfaction 1369 the axon that projects to the glomerulus. It still remains to be elucidated, however, as to how a receptor expressed in an olfactory neuron plays a role in olfactory axon targeting to a specific glomerulus. The axons of VNO neurons also synapse in the glomeruli of the accessory olfactory bulb. In the main olfactory bulb, a single mitral cell that receives a sensory signal from an olfactory neuron is connected to a single glomerulus, whereas a single mitral cell is connected to multiple glomeruli in the accessory olfactory bulb. It is generally believed that the VNO sensory system reflects the primitive form of olfactory systems in vertebrates.
Olfactory Signal Transduction To date, the molecular mechanism of olfactory signal transduction in the main olfactory epithelium is well established. On sensing a ligand (an odor), the G-protein-coupled seven-transmembrane domain receptor is activated, which in turn activates G-protein Gaolf. Consequently, the activated form of G-protein stimulates adenylyl cyclase to increase the intracellular concentration of cAMP. Then, the binding of cAMP opens a cyclic nucleotide-gated cation channel, which leads to depolarization of olfactory neurons. In the VNO, sensory signaling is still unknown, although several signaling molecules that are different from those used in the main olfactory epithelium are implicated. When the same odor is sensed for some time, the response to that odor becomes diminished. This phenomenon is called olfactory adaptation. Electrophysiological studies demonstrated that the continuous stimulation of olfactory neurons decreases the open frequency of ion channels. Olfactory adaptation requires extracellular calcium, and can be diminished when EGTA is present inside the olfactory neuron. Thus, calcium influx induced by olfactory sensation causes an increase in intracellular calcium concentrations, which is thought to inhibit the olfactory response by modifying the olfactory signaling pathway. What then is the target molecule for calcium modification? Recent studies indicate that calcium directly modifies cAMP-gated cation channels, thereby decreasing the channels' sensitivity to cAMP. Also, there is evidence to suggest that the sensitivity of olfactory receptors is modulated by phosphorylation by kinases.
Genetic Approaches to Studying Olfaction: C. elegans as Model System Caenorhabditis elegans is a 1 mm-long, free-living nematode that lives in soil. It is quite likely that
C. elegans depends heavily on olfactory cues to find and stay near its food source, bacteria, in its natural habitat. C. elegans was found to sense, discriminate, and adapt to a variety of odors using only six olfactory receptor neurons of three types; these are situated in the head sensory organs called amphid sensila. The C. elegans nervous system consists of only 302 neurons, the wiring system of which based on ultrastructural analysis has been revealed in its entirety. The short life cycle, the ease of culturing in the laboratory, and the ease with which genetic crosses by mating can be produced make this small worm a powerful genetic model organism. As in vertebrates, olfactory receptors in C. elegans are found to be G-protein-coupled seven-transmembrane domain proteins that are encoded by about 1000 genes. Of these, nearly 400 genes are thought to encode chemosensory receptors, which consist of olfactory and gustatory receptors. Thus, the involvement of a large number of predicted olfactory receptors in the C. elegans olfactory system is similar to that observed in vertebrate olfactory systems, but there are differences in other respects. Since there are only six olfactory neurons in C. elegans, each one is likely to express multiple olfactory receptors, which is consistent with the results from expression analysis for some of the olfactory receptors. As described above, the C. elegans olfactory system is in contrast to the mammalian olfactory system, in which each olfactory neuron seems to express a single type of olfactory receptor. The C. elegans ODR-10 protein, a predicted G-protein-coupled transmembrane domain protein, was the first olfactory receptor to be functionally revealed by genetic analysis. The ODR-10 receptor is expressed only in a single type of olfactory neuron, AWA, and interacts with the odorant diacetyl. Of the three types of olfactory neurons that mediate olfactory responses in C. elegans, the AWA and AWC neurons detect attractive cues, and the AWB neurons detect repulsive cues. An interesting experiment was carried out in which the ODR-10 receptor was ectopically expressed only in the AWB neurons that usually induce aversion responses. When the odorant diacetyl was applied to the transgenic animals expressing ODR-10 only in the AWB olfactory neurons, an aversive response was induced. This result suggests that the olfactory neuron and not the olfactory receptor determines olfactory responses in C. elegans. Olfactory signaling in the AWB and AWC neurons is found to be similar to that of mammalian olfactory neurons, since cyclic nucleotide-gated cation channels appear to function in the last step of olfaction in these neurons. In the AWA neurons, the OSM-9 protein, the capsaicin receptor-like cation channel, is found to be
1370
O nc o g en e s
essential, instead of the cyclic nucleotide-gated channel. In addition to these molecules, other components that are required for olfactory signaling have been identified and are gradually becoming specified through genetic analysis. Although the olfactory system is essentially conserved throughout vertebrates and invertebrates, future genetic analysis of the C. elegans olfactory system will reveal further important similarities and differences in olfaction across species.
Further Reading
Buck LB (2000) The molecular architecture of odor and pheromone sensing in mammals. Cell 100: 611±618. Mombaerts P (1999) Molecular biology of odorant receptors in vertebrates. Annual Review of Neuroscience 22: 487±509. Mori I (1999) Genetics of chemotaxis and thermotaxis in the nematode Caenorhabditis elegans. Annual Review of Genetics 33: 399±422.
See also: Neurogenetics in Caenorhabditis elegans
Oncogenes N Haites Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0925
Definition During normal growth and differentiation, cell proliferation is regulated by growth factors that interact with specific receptors on the plasma membrane and via subsequent reactions eventually lead to alterations in gene expression. The proteins involved in these biochemical steps are the products of protooncogenes, which are normal cellular genes. If these proto-oncogenes are inappropriately activated, they become oncogenes and are involved in tumor development. Most oncogene protein products function in the signaling pathways that regulate cell proliferation in response to growth factor stimulation. These products include growth factors, growth factor receptors, signal transducers, and transcription factors,
Table 1 Events producing oncogene activation
Examples
Oncogene amplification
Amplification of the N-myc gene is frequently present in late stage tumors and is associated with the progression of neuroblastomas to increased levels of malignancy
Activation of oncogenes by transposition to an active chromatin domain
The overproduction of an oncogenic product may also occur by loss of transcriptional control through chromosomal translocation, as typified by the t(8;14) translocation seen in 75% of patients with Burkitt's lymphoma. The translocation causes the myc oncogene on chromosome 8 to become positioned next to an immunoglobulin gene, e.g., the heavy chain on chromosome 14. The constitutive expression of the transposed myc gene after the translocation thereby leads to an inappropriately high level of gene product
Activation by point mutation
In members of the ras family, activating single-base substitutions cause amino acid changes at positions 12, 13, and 61 in a wide range of human tumors, with an overall incidence of 10±15%, but as high as 95% in pancreatic carcinomas. These substitutions alter the structure of the normal protein, resulting in abnormal activity of the guanine nucleotide-binding proteins that they encode
Activation by production of chimeric gene products
Oncogenes can also be activated by chromosomal translocation resulting in the production of a fusion protein. The best known tumor-specific chromosomal rearrangement producing the small acrocentric Philadelphia chromosome is seen in 90% of patients with CML. This chromosome is produced by a balanced reciprocal 9; 22 translocation. The translocation joins most of the abl gene on to a gene called bcl (breakpoint cluster region) on chromosome 22, thereby creating a novel fusion gene. This results in both aberrant activity and subcellular location of the Abl protein tyrosine kinase, thereby leading to cell transformation
Olfaction
Olfaction I Mori Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0924
Olfaction is a major sense in animals. The detection of volatile chemical compounds is an important attribute for any animal to survive and reproduce in the natural environment. Different animals utilize different types of olfactory organs. For example, humans detect odors through the olfactory epithelium of the nose, whereas most insects detect odors through their antennae. Although olfactory systems are divergent throughout evolution, olfactory receptor neurons possess common properties and structure. It is intriguing to realize that even fish have an olfactory organ that is distinct in function and structure from its gustatory organ, but is similar to the olfactory organ of mammals. Similarly, molecular analysis of olfaction reveals that on sensing olfactory stimuli, essentially the same signaling events occur in vertebrates as in invertebrate species. In this review, the mammalian olfactory system is described as an example of vertebrate olfactory systems. This review also briefly considers the olfactory system of the nematode Caenorhabditis elegans, which is one of the bestcharacterized sensory systems in invertebrates at molecular and cellular levels.
Olfaction in Mammals The mammalian olfactory system is one of the most evolved sensory systems. Even humans have the ability to detect and discriminate at least 10 000 different odorants. In mammals, odors are sensed in the olfactory epithelium of the nasal cavity, where olfactory neurons are distributed in such a way that the sensory cilia of each olfactory neuron face the nasal cavity. Olfaction first occurs in the sensory cilia of olfactory neurons, and the generated olfactory signals are transmitted to the olfactory cortex and to other area of the brain through synaptic connections of olfactory neurons with downstream neurons, such as mitral or tufted cells, in the main olfactory bulb. In most cases, mammals have a second olfactory organ called the vomeronasal organ (VNO), which is situated on the lower side of the nasal cavity. The VNO detects pheromones and is particularly important for some animals such as mice, in which pheromones play a key role in controlling their behaviors. Olfactory sensation in the VNO is transmitted to the accessory olfactory bulb, which occupies a distinct area of the main olfactory bulb. Since the areas of brain
that receive signals from the accessory olfactory bulb are different from those that receive signals from the main olfactory bulb, the effects of odorant sensation and pheromone sensation cause different behavioral and emotional outcomes.
Olfactory Receptors It is understood that all olfactory receptors are found to be G-protein-coupled seven-transmembrane domain receptors and are usually encoded by the largest gene family in any animal. In mammals, there are about 1000 genes that encode olfactory receptors in the olfactory epithelium. In the VNO, there are two olfactory receptor families: the V1R family, which consists of 35 members; and the V2R family, which consists of 150 members. These two receptor families are likely to detect pheromones. The members of olfactory receptor families are very diverse in their amino acid sequences, which is consistent with the fact that animals detect a large number of odorants. Perhaps, each odorant interacts with and activates a single or small subset of olfactory receptor proteins.
Organization of Olfactory Receptors There are a number of interesting questions regarding organization of olfactory receptors. First, molecular and cellular studies indicate that each olfactory neuron seems to express only a single type of olfactory receptor. How a single gene is chosen from among 1000 olfactory receptor-coding genes in a particular olfactory neuron remains a mystery. Second, recent analysis has revealed spatially distinct expression of genes encoding olfactory receptors in the olfactory epithelium. Although these receptors are diverse in their makeup, they are categorized on the basis of the zone in which they are expressed. There are four zones and each olfactory receptor is expressed in one of these zones. The function of the zonal organization is unknown. In the VNO, there appear to be two zones: one that expresses members of the V1R family, and the other that expresses members of the V2R family. On the surface of the main olfactory bulb, there are about 2000 units of structures called glomeruli, where axons of olfactory neurons synapse onto downstream neurons, such as mitral cells. Interestingly, each olfactory neuron projects its axon toward a specific glomerulus. Furthermore, olfactory neurons that express the same type of olfactory receptors send their axons to the same glomerulus. How is this precise olfactory projection established? In one model, the olfactory receptor per se is thought to be a determinant for projection to a particular glomerulus, since messages (mRNAs) for olfactory receptors have been unexpectedly detected in
Olfaction 1369 the axon that projects to the glomerulus. It still remains to be elucidated, however, as to how a receptor expressed in an olfactory neuron plays a role in olfactory axon targeting to a specific glomerulus. The axons of VNO neurons also synapse in the glomeruli of the accessory olfactory bulb. In the main olfactory bulb, a single mitral cell that receives a sensory signal from an olfactory neuron is connected to a single glomerulus, whereas a single mitral cell is connected to multiple glomeruli in the accessory olfactory bulb. It is generally believed that the VNO sensory system reflects the primitive form of olfactory systems in vertebrates.
Olfactory Signal Transduction To date, the molecular mechanism of olfactory signal transduction in the main olfactory epithelium is well established. On sensing a ligand (an odor), the G-protein-coupled seven-transmembrane domain receptor is activated, which in turn activates G-protein Gaolf. Consequently, the activated form of G-protein stimulates adenylyl cyclase to increase the intracellular concentration of cAMP. Then, the binding of cAMP opens a cyclic nucleotide-gated cation channel, which leads to depolarization of olfactory neurons. In the VNO, sensory signaling is still unknown, although several signaling molecules that are different from those used in the main olfactory epithelium are implicated. When the same odor is sensed for some time, the response to that odor becomes diminished. This phenomenon is called olfactory adaptation. Electrophysiological studies demonstrated that the continuous stimulation of olfactory neurons decreases the open frequency of ion channels. Olfactory adaptation requires extracellular calcium, and can be diminished when EGTA is present inside the olfactory neuron. Thus, calcium influx induced by olfactory sensation causes an increase in intracellular calcium concentrations, which is thought to inhibit the olfactory response by modifying the olfactory signaling pathway. What then is the target molecule for calcium modification? Recent studies indicate that calcium directly modifies cAMP-gated cation channels, thereby decreasing the channels' sensitivity to cAMP. Also, there is evidence to suggest that the sensitivity of olfactory receptors is modulated by phosphorylation by kinases.
Genetic Approaches to Studying Olfaction: C. elegans as Model System Caenorhabditis elegans is a 1 mm-long, free-living nematode that lives in soil. It is quite likely that
C. elegans depends heavily on olfactory cues to find and stay near its food source, bacteria, in its natural habitat. C. elegans was found to sense, discriminate, and adapt to a variety of odors using only six olfactory receptor neurons of three types; these are situated in the head sensory organs called amphid sensila. The C. elegans nervous system consists of only 302 neurons, the wiring system of which based on ultrastructural analysis has been revealed in its entirety. The short life cycle, the ease of culturing in the laboratory, and the ease with which genetic crosses by mating can be produced make this small worm a powerful genetic model organism. As in vertebrates, olfactory receptors in C. elegans are found to be G-protein-coupled seven-transmembrane domain proteins that are encoded by about 1000 genes. Of these, nearly 400 genes are thought to encode chemosensory receptors, which consist of olfactory and gustatory receptors. Thus, the involvement of a large number of predicted olfactory receptors in the C. elegans olfactory system is similar to that observed in vertebrate olfactory systems, but there are differences in other respects. Since there are only six olfactory neurons in C. elegans, each one is likely to express multiple olfactory receptors, which is consistent with the results from expression analysis for some of the olfactory receptors. As described above, the C. elegans olfactory system is in contrast to the mammalian olfactory system, in which each olfactory neuron seems to express a single type of olfactory receptor. The C. elegans ODR-10 protein, a predicted G-protein-coupled transmembrane domain protein, was the first olfactory receptor to be functionally revealed by genetic analysis. The ODR-10 receptor is expressed only in a single type of olfactory neuron, AWA, and interacts with the odorant diacetyl. Of the three types of olfactory neurons that mediate olfactory responses in C. elegans, the AWA and AWC neurons detect attractive cues, and the AWB neurons detect repulsive cues. An interesting experiment was carried out in which the ODR-10 receptor was ectopically expressed only in the AWB neurons that usually induce aversion responses. When the odorant diacetyl was applied to the transgenic animals expressing ODR-10 only in the AWB olfactory neurons, an aversive response was induced. This result suggests that the olfactory neuron and not the olfactory receptor determines olfactory responses in C. elegans. Olfactory signaling in the AWB and AWC neurons is found to be similar to that of mammalian olfactory neurons, since cyclic nucleotide-gated cation channels appear to function in the last step of olfaction in these neurons. In the AWA neurons, the OSM-9 protein, the capsaicin receptor-like cation channel, is found to be
1370
O nc o g en e s
essential, instead of the cyclic nucleotide-gated channel. In addition to these molecules, other components that are required for olfactory signaling have been identified and are gradually becoming specified through genetic analysis. Although the olfactory system is essentially conserved throughout vertebrates and invertebrates, future genetic analysis of the C. elegans olfactory system will reveal further important similarities and differences in olfaction across species.
Further Reading
Buck LB (2000) The molecular architecture of odor and pheromone sensing in mammals. Cell 100: 611±618. Mombaerts P (1999) Molecular biology of odorant receptors in vertebrates. Annual Review of Neuroscience 22: 487±509. Mori I (1999) Genetics of chemotaxis and thermotaxis in the nematode Caenorhabditis elegans. Annual Review of Genetics 33: 399±422.
See also: Neurogenetics in Caenorhabditis elegans
Oncogenes N Haites Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0925
Definition During normal growth and differentiation, cell proliferation is regulated by growth factors that interact with specific receptors on the plasma membrane and via subsequent reactions eventually lead to alterations in gene expression. The proteins involved in these biochemical steps are the products of protooncogenes, which are normal cellular genes. If these proto-oncogenes are inappropriately activated, they become oncogenes and are involved in tumor development. Most oncogene protein products function in the signaling pathways that regulate cell proliferation in response to growth factor stimulation. These products include growth factors, growth factor receptors, signal transducers, and transcription factors,
Table 1 Events producing oncogene activation
Examples
Oncogene amplification
Amplification of the N-myc gene is frequently present in late stage tumors and is associated with the progression of neuroblastomas to increased levels of malignancy
Activation of oncogenes by transposition to an active chromatin domain
The overproduction of an oncogenic product may also occur by loss of transcriptional control through chromosomal translocation, as typified by the t(8;14) translocation seen in 75% of patients with Burkitt's lymphoma. The translocation causes the myc oncogene on chromosome 8 to become positioned next to an immunoglobulin gene, e.g., the heavy chain on chromosome 14. The constitutive expression of the transposed myc gene after the translocation thereby leads to an inappropriately high level of gene product
Activation by point mutation
In members of the ras family, activating single-base substitutions cause amino acid changes at positions 12, 13, and 61 in a wide range of human tumors, with an overall incidence of 10±15%, but as high as 95% in pancreatic carcinomas. These substitutions alter the structure of the normal protein, resulting in abnormal activity of the guanine nucleotide-binding proteins that they encode
Activation by production of chimeric gene products
Oncogenes can also be activated by chromosomal translocation resulting in the production of a fusion protein. The best known tumor-specific chromosomal rearrangement producing the small acrocentric Philadelphia chromosome is seen in 90% of patients with CML. This chromosome is produced by a balanced reciprocal 9; 22 translocation. The translocation joins most of the abl gene on to a gene called bcl (breakpoint cluster region) on chromosome 22, thereby creating a novel fusion gene. This results in both aberrant activity and subcellular location of the Abl protein tyrosine kinase, thereby leading to cell transformation