Olfactory mechanisms in Drosophila melanogaster

500

Olfactory mechanisms in Drosophila

melanogaster

Dean P Smith Genetic approaches are beginning to provide valuable insights into the function of specific gene products in olfaction. Analysis of Drosophila

mutants that affect olfactory

responses are defining components of the olfactory signaling mechanisms. Mutations in the genes paralytic and Scutoid cause olfactory defects, as do mutations in genes encoding products that mediate visual responses. of the family of invertebrate

In addition, members

odorant-binding

been identified in Drosophila

proteins have

and may play an important role

in the olfactory process.

Addresses Department of Pharmacology, University of Texas Southwestern Medical Canter, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9111, USA; e-mail: Smith1 [email protected] Abbreviations inositol trisphosphate IP3 paralytic para PIP, phosphatidylinositol bisphosphate protein kinase C PKC PLC phospholipase C rdg8

retinal degeneration

B

Current Opinion in Neurobiology 1996, 6:500-505 0 Current Biology Ltd ISSN 0959-4388

Introduction Drosophila melanogaster is an attractive

model system in which to study the complex mechanisms underlying olfactory signal transduction and information processing. They are able to detect and respond to a wide variety of odorants, and simple behavioral assays can be used to assess olfactory function in these animals because specific odorants elicit stereotypical behavioral responses. In addition, Drosophila is the most easily manipulated genetic animal model system that processes odor information in glomerular synaptic networks similar to those in higher animals. We are beginning to gain insight into olfactory mechanisms in Drosophila by analyzing mutants with abnormal chemosensory function, and by correlating this information with molecular information about the gene products disrupted in those mutants. In this review, I will describe recent progress on genes that fall into three classes: genes affecting many processes, including olfaction; genes that generate products common to several sensory systems; and genes with expression restricted to the olfactory system. The recent identification of signal-transduction molecules expressed in vertebrate olfactory systems has renewed interest in this poorly understood sensory modality.

Genes encoding olfactory G proteins, adenylyl cyclases, cyclic-nucleotide-gated cation channels and a large family of putative odorant receptors have provided insight into how vertebrate olfactory systems might recognize and transduce odors [l-4]. It has been proposed that each of the 100 million olfactory neurons expresses a single member of the 1000 or so different receptor genes. Neurons expressing the same receptor gene synapse at the same site in the olfactory bulb [5,6]. If different odors selectively activate different sets of receptors, then the pattern of activity occurring in the olfactory bulb would be unique for each odor, providing an explanation for how odorant information is initially encoded [5,6]. Yet, direct proof that these receptors or signaling components actually mediate odor responses in intact animals is lacking. Olfactory model systems (such as Drosophila) amenable to genetic analysis and simple assays of olfactory behavior can provide essential information about the functions of specific olfactory gene products in intact animals. The principal olfactory organs in adult flies are the funiculi or third antenna1 segments (reviewed in [7]). These structures are covered with several hundred sensory hairs (sensilla) that are divided into three morphologic classes: the trichoid, basiconic and the coeloconic sensilla. All of these sensilla are thought to mediate olfactory responses. Insect sensilla are hollow and filled with fluid (sensillar lymph). The dendrites of the olfactory neurons project into the fluid-filled core of the sensilla [8]. The composition of the sensillar lymph is regulated by non-neuronal support cells that secrete a variety of ions and proteins into the fluid-filled sensilla shafts. Each of the approximately 2000 olfactory neurons project their axons directly to the bilateral antenna1 lobes, which are the Drosophila equivalent of the olfactory bulb. Each neuron synapses exclusively in one of the 35 glomeruli, either ipsilaterally or bilaterally [7,9]. Antenna1 lobe output is routed to higher-brain structures, including the mushroom bodies, where memory is thought to be consolidated [lo]. Different odorants induce different patterns of glomerular activation in the antenna1 lobes [11,12], suggesting that specific subsets of olfactory neurons are activated by different odorants and that the brain might hold a topographic odorant map.

Genes with general neural functions olfaction

affecting

The small size and short reproductive cycle of Drosophila combined with olfactory-based behavioral screens allow the rapid generation and identification of mutants defective in olfactory responses. Several laboratories have isolated mutants with a variety of olfactory defects (see Table 1). These deficits range from reduced attraction to

Olfactory mechanisms in Drosophila melanogaster Smith

specific compounds to reduced responses to all odorants [13-161. Yet, the molecular nature of the genes affected in these mutants remains largely unknown. olfD/smellblind channel

mutants affect a Drosophila sodium

One of the more interesting olfactory mutants isolated on the basis of defective olfactory behavior is ol@/smeifbiind. Mutants affecting this gene have been isolated independently in two laboratories [14,15]. These mutants have reduced (but not absent) sensitivity to a wide range of odorants. The mutants were mapped to a region of the X chromosome known to encode the principal &-osopkla sodium channel gene paralytic (para) [17,18]. As might be expected, strong para alleles are lethal. Yet, most weak para mutants become reversibly paralyzed at elevated

501

temperatures [19], probably as a result of the overall reduction in functional sodium channel density on neurons [‘ZO]. Many combinations of para and olpfsmeflb/ind fail to complement the lethality associated with strong para mutants, and two o/JD/smel/bLndalleles with molecular lesions in the para locus have been identified [Zl]. These data strongly suggest that ol@/smelfbiind and para mutations affect the same gene. Interestingly, the olfl)/smel/blindmutants do not display the paralysis phenotype, and non-lethal para mutants do not have olfactory defects. The most likely explanation is that the two classes of para mutants @ara and o/&Vfsme//blind) affect different splicing variants of the para sodium channel expressed in different tissues (para is known to encode at least 10 splicing variants [17,21]). Olfactory

Table 1 Phenotype and cytogenetic locations of numerous Drosophila mutants with defects in olfactory responses. Mutant

Cytogenetic locatIon*

offA

788-01

OH6

2B17-C2

OlfC

7Dl-6

olfDl

14C9-Dl

smellblindi para

Phenotype

Genetics

Reduced

Recessive

1151

Recessive

1151

sensitivity to benzaldehyde

Reduced sensitivity to benzaldehyde, and to other aldehydes

Temperature

References

sensitive

Recessive

1151

Reduced sensitivity to multiple odorants; reduced electroantennogram

Recessive

[15,481

Reduced

sensitivity to isoamyl acetate

olfE

7C9-Dl

Reduced

sensitivity to benzaldehyde

Recessive

1151

oifF

2El-3C2

Reduced

sensitivity to benzaldehyde

Recessive

[I 51

acj6

13A

Reduced

sensitivity to multiple odorants;

Recessive

[491

Recessive

[‘W501

reduced

rdgB/ otal

12A

Reduced

electroantennogram sensitivity to multiple odorants;

also a retinal degeneration

mutant

norpA

4B-C

Reduced maxillary palp responses to several odorants; also a visual mutant

Recessive

ota2

1814

Reduced

sensitivity to propionic acid

Recessive

[16l

Dominant

t161

ota3

X

Reduced sensitivity to propionic acid, and to ethyl acetate

ota5

X

Reduced sensitivity to propionic acid, and to benzaldehyde

ota7

lB14

3018

3D

Scutoid

odA

35A-C

2

[32”]

[151 Semi-dominant

[I 61

Recessive

(511

Reduced responses to short-chain acetate esters and ketones

Dominant

[26”]

Enhanced

Unknown

WI

Reduced response to ethyl acetate; visual defects as well Reduced

sensitivity to benzaldehyde

responses

to ethyl acetate

*All genes listed are X-linked except Scutoid and odA, which are on the second chromosome. the chromosome in which the gene resides.

Cytogenetic

location is denoted

by the interval along

502

Sensory systems

neurons

may specifically express splicing variants of the channel affected in o/@/smellb/ind mutants, resulting in a reduced ability to generate action potentials in those neurons. Characterization of the para splicing products in wild-type and mutant animals, and precise mapping of olfDlsme//blind point mutations to specific exons will clarify this issue.

para sodium

Scotoid mutants have specific olfactory defects Scutoid is a reciprocal transposition genomic rearrangement [22,23] generated in an X-ray screen that results in the

developmental loss of many large mechanosensory bristles [24]. The resulting fusion between the no-ace//B and snai/ loci is responsible for the bristle phenotype [22,25]. Recently, the olfactory responses of Scutoid mutants were carefully examined and found to have surprisingly specific deficits [26**]. Antenna! responses to seven odorants revealed reduced responses to short-chain acetate esters and ketones. Scutoid mutants have peak responses that are 2.5fold below normal flies for acetone, and fourfold below normal for ethyl acetate. The loss of responsiveness correlated well with the length of the side chain. For example, acetone and Z-butanone responses are weak in the Scutoid mutants, whereas 3-pentanone responses are intermediate, and Z-heptanone responses are similar to those of the wild-type fly. Responses to ethyl acetoacetate are also reduced, but only in the proximal quadrants of the third antenna! segment. Remarkably, responses to other odorants are normal, as are larval olfactory responses. Why do Scutoid mutants have these olfactory defects? Subsets of sensilla that mediate these odorant responses might be absent in Scutoid mutants. However, the number and types of sensilla on the third antenna! segments of Scutoid flies appear grossly normal in scanning electron micrographs [26”]. Alternatively, neurons or accessory cell types that compose a functional sensillum or specific olfactory gene products (such as odorant-binding proteins or odorant receptors specific for the short-chain acetates and ketones) might be missing. It will be critical to direct future experiments towards determining whether the olfactory defects in Scutoid mutants result from a loss of cells or a change in fate determination, or from a specific defect in signal transduction.

The visual and olfactory systems share genes The signaling mechanisms mediating olfaction in Drosophila are largely a mystery. In other insects, inositol trisphosphate (IP$ has been implicated as one of the second-messenger signaling molecules mediating olfactory responses [27]. Interestingly, the DrosopMa visual system uses IP3 as a second messenger, and many of the components of the visual signal-transduction machinery have been functionally identified through analysis of mutants with defective visual responses (reviewed in [B]). In Drosophila photoreceptors, light molecules that activate G proteins

activates rhodopsin and, subsequently,

phospholipase C (PLC). The latter cleaves the membrane lipid phosphatidylinositol bisphosphate (PIPz) into IP3 and diacylglycerol. These second messengers trigger activation and regulation of the light response [28]. Given the central role of PIP2 in phototransduction, it is not surprising that many mutants with defective light responses affect genes encoding components of PIP2 metabolism [ZS]. As olfactory responses may also use IP3, many of these mutants might affect olfactory responses as well. For example, strong mutants in the nolpA gene abolish the light response [29,30]; this gene encodes the phosphatidylinositol-specific PLC that is activated in response to light [31]. It has recently been found that ~OQIA odorant responses for a variety of odors, measured from the maxillary palps (accessory olfactory organs), are reduced [32**]. Responses from the antenna, however, appear normal, These results suggest, therefore, that products of the no@A gene mediate all of the light response and a subset of the olfactory responses. A second gene involved in vision and IP3 metabolism is retina/ degeneration R (rdgB). This gene encodes a phosphatidylinositol transfer protein [33]. rdgB mutants undergo light-dependent photoreceptor cell degeneration, and alleles have been isolated in both visual and olfactory mutant screens [16,29]. Comparison of the odor-induced electrical responses of the maxillary palps in rdgB and wild-type flies indicates that rdgB mutants have a delay in repolarization back to resting membrane potential for multiple odorants [34]. This indicates that, like norpA, rdgB gene products are required in both the visual and olfactory systems. A third systems

gene shared between the visual and olfactory in Drosophila is the G-protein a-subunit gene dC,a. G-protein-coupled receptors expressed in subsets of olfactory neurons have been identified in a number of vertebrate animals, including humans. Recently, a family of G-protein-coupled receptors have been identified in the invertebrate Caenorhabditis elegans, and one has been demonstrated to mediate a specific odor response in the intact animal [35**]. A similar odorant receptor gene family has yet to be identified in DrosopMa, but at least two G-protein a subunits are present in Drosophila olfactory neurons, a G,a subtype [36] and a G,a subtype [37*]. Interestingly, the G4a subtype is expressed only in a subset of olfactory neurons. The Drosophila dC,a gene was originally identified on the basis of its expression in the visual system [38]. The predominant protein encoded by this gene, dGqa-1, mediates visual responses [39-l. However, the dGqa gene encodes an alternate form generated by differential splicing; this form, dG,a-3, is expressed in the antenna and maxillary palps in subsets of olfactory neurons, in olfactory support cells, and in neurons of the central nervous system [37*]. The fact that dGqa-3 is only expressed in a subset of olfactory neurons suggests that it

Olfactory mechanisms in

performs a specific function, perhaps mediating a subset of odorant responses. Because G-protein ~1subunits of the q class are known to activate PLC, thereby triggering IPJ production, dGga-3 could activate norpA gene products in the DrosopMa olfactory system. If true, dGp-3 mutants would be expected to have the similar olfactory deficits as norpA mutants. Screens designed to recover dGqa-3 mutants are under way to test this possibility. Together, these data support the idea that IP3 mediates visual and olfactory responses, and these two sensory systems share genes encoding important components. It is worth noting, however, that some visual components of the IP3 cascade are not shared by the olfactory system. Eye-PKC, the visual specific protein kinase C encoded by the inaC gene, is required for deactivation and desensitization of the photoresponse [40]. However, eye-PKC antisera does not detect antigen in the antenna or maxillary palps (DP Smith, unpublished data).

A family of odorant-binding present in Drosophila

proteins are

Odorant-binding proteins are found in both vertebrate and invertebrate animals, although they arise from different gene families. In both cases, they are expressed and secreted by non-neuronal support cells into the fluid that bathes the olfactory neuron dendrites (reviewed in [41]). Invertebrate members were first identified in moths. Female moths release pheromones that can be detected by males several miles away [42]. Moth pheromone-binding proteins are expressed exclusively in the antennae of male moths, and bind with high affinity to female pheromones [43]. Related proteins are found in both male and female antennae, suggesting these proteins may play a role in the detection of general odors [44,45]. Because these binding proteins are not synthesized in the olfactory neurons but are secreted into the sensillar fluid by support cells, they probably function upstream of olfactory neuron activation in the olfactory process. Possible functions include solubilization or concentration of odorants in the sensilla fluid, protection of odorant molecules from odorant degradation enzymes in sensillar lymph, or presentation of odorant to receptors on the olfactory neuron dendrites. A role in odorant degradation or removal has also been postulated (reviewed in [$I]). Six members of this family have been reported in DrosopMa so far [46,47]. The total number of odorantbinding protein genes expressed in the antenna is difficult to estimate. All members cloned so far share the chemosensory-specific distribution and structural similarities (including six cysteine residues with conserved spacing and amino-terminal signal sequences for secretion). However, the low sequence homology (-20% amino acid identity) precludes simple methods to identify additional

Drosophila melanogaster Smith

503

family members, such as low-stringency hybridization and degenerate primer PCR approaches. This family could potentially be quite large. Messenger RNA localization studies of the cloned members demonstrate that all are expressed equally in males and females [46,47], suggesting that all six are odorant-binding proteins (as opposed to pheromonebinding proteins). These expression studies show that the binding-protein genes are expressed in different, overlapping zones on the third antenna1 segment [46,47]. Whether or not they are expressed in specific subsets of the three classes of sensilla is unknown; however, the primary sequence diversity combined with the restricted expression patterns suggests that they may perform an odorant-specific function. Given that insects have anatomically isolated their olfactory neuron dendrites in separate sensilla, one intriguing possibility is that the repertoire of binding proteins expressed in the sensillar lymph may act as a ‘pre-receptor’ screening mechanism, to limit the number of odorants that can interact with an olfactory neuron. Thus, odorantbinding proteins may partially determine the odorant specificity of the olfactory neurons. We have recently obtained a DrosopMa odorant-binding protein mutant in an unreported member of this family. The olfactory deficits resulting from the loss of this gene product support this model (DP Smith, abstract 11, Neurobiology of Drosophila, Cold Spring Harbor, October 1995).

Conclusions Analysis of olfactory defects in mutant animals is a powerful approach for obtaining information about the function of specific gene products in the olfactory process. Mutations in para and Scutoid indicate that these genes play an important role in olfactory neuron physiology and development. Olfactory defects resulting from mutations in genes encoding proteins that also mediate visual responses indicate that these genes are utilized for multiple sensory processes. Odorant-binding proteins may help determine the odorant sensitivity of olfactory neurons in DrosopMa. Finally, some the most interesting mutants isolated so far affect specific subsets of odorant responses but have yet to be molecularly characterized. Determination of the nature of the gene products affected in these mutants and generation of mutants in identified olfactory-specific genes will provide further insight into the mechanisms underlying olfaction in DrosopMa.

Acknowledgements Work reported from the author’s laboratory was supported by grants from the National Institute of Deafness and Other Communicative Disorders (NIDCD).

504

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