ood sources and territories, but also to perceive signals rele-ant for social interaction and reproduction. Odor molecules areetected by a few million olfactory sensory neurons (OSNs)ocated in the epithelium that lines the nasal cavity. The initial
tep involves the interaction of odorous compounds with odoranteceptors (ORs) in the ciliary membrane of the OSNs. Mammalsave a large repertoire of ORs, seven-transmembrane proteins
J. Strotmann, H. Breer / Seminars in Cell & Developmental Biology 17 (2006) 402–410 403
Fig. 1. Pattern of connectivity between the olfactory epithelium and the bulb. (A) X-Gal stained whole-mount preparation of a transgenic mouse in which OSNsexpressing the OR mOR18-2 co-express lacZ. The cells are restricted to the dorsal zone of the epithelium, axons converging onto the glomerulus on the medialhemisphere are visible. (B) Schematic representation of the zone-to-domain topography between the olfactory epithelium and the bulb. Cells positioned withindistinct zones of the epithelium send their axons to a corresponding domain of the bulb. The boundary between the most dorsal zone and the remaining zones in thee certa
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hich are encoded by a gene family comprising more than 1000ifferent members [1–5]. The capacity of the olfactory system toecognize and discriminate literally tens of thousands of volatileompounds is based on the principle that each odorous com-ound elicits a chemospecific response pattern of multiple OSNopulations. The characteristic response spectrum of each OSNopulation is determined by its particular OR [6]. OSNs express-ng the same OR are arranged in characteristic spatial patternsithin the OE, most of them being broadly dispersed within
haracteristic zones [7–11]. Although it is generally believedhat signal transduction in OSNs is mediated by the adenylylyclase/cAMP cascade, a subpopulation of cells lacks the keylements of this signaling pathway; these cells express a sub-ype of the transmembrane receptor guanylyl cyclase, termedC-D which has been suggested to interact with olfactory cues
12].Olfactory information is conveyed via the OSNs axons to
he olfactory bulb (OB). Each OSN extends a single axonhat synapses onto bulb neurons in a characteristic sphericaleuropil, called glomerulus. Glomeruli are neuropil-networksf synaptic interaction between the axon terminals of OSNsnd the dendritic trees of mitral/tufted cells, the OB projec-ion neurons and local interneurons (see article by Wachowiaknd Shipley, this issue). In mice there are supposed to bebout 1800 glomeruli that cover the surface of the OB [13].eurons which are segregated in the epithelium project toistinct regions of the bulb, such that the spatial topogra-hy of the nasal epithelium is preserved in the glomerularheet [14–16]; following the principle of a “zone-to-domain”-rojection [17] (Fig. 1). This arrangement is superimposed byhe OR-related convergence of axons to specific glomeruli.eceptor-specific convergence was initially observed by visu-lizing mRNA of ORs in OSN axon terminals [18,19]. These of genetically manipulated mice which co-express axonal
arkers together with the OR allowed to visualize that the
xons of all cells expressing the same OR converge [20,21].ith only few exceptions [22,23] each OR-specific OSN
opulation targets two glomeruli, one located in the medial,
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he other in the lateral hemisphere of each bulb. This con-ergence of receptor-specific OSN populations onto distinctlomeruli generates a chemospecific map which is consid-red as the basis for a combinatorial processing of odorant-pecific molecular entities leading to the identification of odors24–28].
The necessity to create precise connections for more than000 populations of OSNs with spatially confined positions inhe OB is a formidable task; questions like how an axon findsts way to the appropriate glomerulus or what makes the axonerminals of receptor-specific OSN-populations coalesce into aommon glomerulus are virtually unanswered. Employing novelpproaches numerous studies of the last few years have openedew avenues for unraveling the principles underlying the chemo-opographic wiring of the olfactory system.
. Emergence and structure of glomeruli
The olfactory system is established and functions during therenatal phase. In mice, first axons contact the telencephalicesicle around embryonic day 13 (E13) [29,30]. Before enter-ng the presumptive OB, the axons of distinct OSNs populationsppear to “wait” for a short time at the surface [29]; this phe-omenon has been proposed to prevent axons from entering theirarget prematurely [31]. Axonal targeting to a specific site withinhe OB is observed as early as E15.5, and initially axons fromparticular OSN population terminate in a rather broad area of
he OB surface [29,30,32]. Studies of transgenic mice in whichSNs expressing highly related ORs were visualized by differ-
nt markers revealed that their axons are intermingled duringhe pre- and perinatal phase [29,33]. Only postnatally the axonsegregate into completely distinct glomerular structures. Thisaturation process requires different time periods, ranging from
nly three days for the “OR37” glomeruli [29] up to 25 days for
he “M72” glomeruli [33].
Axons approach their final destination through the outer partf the outer nerve layer (ONL) where the majority of axonsruise individually; as they enter the inner part of the ONL
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hey fasciculate, first into small bundles that merge into largerables; however, also individual axons can enter the appro-riate glomerulus [34]. Finally, an extraordinarily high pre-ision of axonal targeting is achieved, even for populationshich express highly related ORs and innervate neighboringlomeruli [29,35]. Bundles of axons passing through neigh-oring glomeruli are frequently observed [29,34], but theres no evidence that they terminate in inappropriate glomeruli.xons approach a glomerulus via different routes and enter
t multiple points. The spatial arrangement of axonal entryoints into a glomerulus appears stochastic and differs for everylomerulus, even for the “sister”-glomerulus in the other bulb32].
Although the spatial arrangement of glomeruli on the surfacef the OB, the glomerular map, was originally considered asnvariant and stereotypic [20], recent analyses provided evidenceor a considerable degree of variability in the arrangement oflomeruli. In some individuals, extra glomeruli exist [30,36]; itas observed that in cases where the number varied, the total vol-me of all receptor-specific glomeruli was nevertheless constant36]. Differentially tagged OR genes leading to different label-ng of the cell populations provided evidence for a significantariability concerning the relative position of distinct glomeruli22]. The original hypothesis that axons of OSNs which expresshe same OR all converge onto common glomeruli has receivedupport from numerous studies and the exploration of severaleceptor subtypes. Vice versa, axons converging onto a particu-ar glomerulus all originate from OSNs which express the sameR [34,37].
.1. Maintenance of the topographic map
The precise wiring of OSNs with their target glomeruli inhe OB is complicated by the fact that each OSN has a limitedife span and that novel OSNs are generated from a popula-ion of basal precursor cells in the OE throughout life [38,39].owever, although OSNs continuously are replaced by new-orn neurons, the spatial map apparently remains constant. Theapacity of newly generated neurons to restore the topographicap was studied by several techniques. When in adult P2-
acZ mice the axons were surgically cut, the newly formed P2xons mistargeted to multiple aberrant glomeruli [40], suggest-ng that the appropriate guidance cues were no longer available.fter a more gentle chemical ablation of the OSNs, a pop-lation which targeted the ventral domain of the OB largelyestored the axonal projection [41]. However, P2 axons whichave to reach more medial and lateral positions on the OB ter-inated in numerous inappropriate glomeruli [42]. Some of
hese errors were refined over time, but there was still consider-ble mistargeting long time after regeneration. Using an elegantenetic approach which allowed to synchronously ablate onlySNs which express P2 and then a renewal of the P2 popu-
ation, it was shown that the axons converged in one or two
lomeruli at a relatively authentical position [43]. The accuratee-establishing of the map indicates that the parameters neces-ary to generate the precise projection map persist throughoutife.
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. The role of neuronal activity in the formation of theap
.1. Odor evoked activity
In other sensory systems the formation of topographic pro-ections during development is generally thought to be dividednto an early phase of intrinsic processes which is activity-ndependent, followed by a refinement phase determined byctivity dependent processes. For the olfactory system, studiesvaluating the wiring process when the olfactory signal transduc-ion cascade was blocked by a knock out of the cyclic nucleotideated (CNG) channel revealed that the projection of P2 and M50xons was correct [44]; however, the projection of M72 axonsas altered to multiple smaller glomeruli [45]. Thus, inhibitionf the transduction process affects the convergence for some, butot for all OSN populations. A remarkable phenotype emergedhen a receptor-specific OSN population was subdivided intone subgroup expressing a defective, and a second subgroupxpressing a functional CNG-channel; these two subgroups sentheir axons into distinct glomeruli [45]. When a large fractionf all OSNs expressed a defective and a small fraction an intactNG-channel, the deficient neurons were slowly and selectivelyepleted from the olfactory epithelium [46]; this occurred onlyhen the epithelium was exposed to odors. It is thought thateficient cells are eliminated due to competition with the wild-ype cells for target sites in a glomerulus. Since this occurs onlyhen OSN are electrically active, a role for activity-dependent
ompetition for the target is evident. Similar observations areade when OSNs form ectopic glomeruli; these are eliminated
nder normal odor exposure but persist after naris closure [47].The segregation of axons from heterogeneous pre-glomeruli
hich are formed early during development is significantly influ-nced by odor-evoked activity; odor deprivation dramaticallylowed down this process [33]. Since naris closure prolongedhe life span of OSNs it was hypothesized that a reduced cellurnover may provide less opportunity for the removal of cellshat ‘mistargeted’ into an inappropriate glomerulus. Thus, thentangling of axons during glomerulus maturation is apparentlyue to a stimulus-promoted elimination of axons by cell death,ather than a selective axonal pruning or a rearrangement ofbers [33].
.2. Effect of reduced excitability and synaptic transmission
Using an elegant genetic approach which allows a conditionalnd cell specific expression of molecules that alter the electricalctivity of OSNs, Yu et al. [48] examined the role of spontaneousctivity for the formation of glomerular maps. Overexpressionf the inwardly rectifying K+-channel Kir2.1 which diminishesxcitability by hyperpolarizing the cells led to a significantlyelayed formation of the map; axons did not enter the bulb untilostnatal day 11. OSN populations that have to project over
onger distances were more affected. The precision of targetingor distinct OSNs was also diminished; cells projected to morelomeruli than normal. In a second paradigm, synaptic transmis-ion was blocked by inhibition of transmitter release. Prevention
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f transmitter release in all OSNs neither altered the number ofells expressing a particular OR, nor the projection and target-ng of their axons. Thus, an overall inhibition (or reduction) ofynaptic activity did not perturb the formation or maintenance ofhe glomerular map. However, when the transmitter release waslocked in only a small subpopulation of OSNs during develop-ent, the axons did form a glomerulus but it was not maintained
nd the neurons were ultimately depleted. Thus, in a competi-ive scenario neurons that do not release neurotransmitter targetorrectly, but fail to maintain stable synaptic contacts and thenradually disappear. These results emphasize that spontaneousctivity and neurotransmitter release are not required for gen-rating the map but rather for an appropriate timing of axonalutgrowth, the precision of targeting and the stability of specificynaptic connections in the bulb.
. Cellular and molecular cues that contribute to guideSN axons
.1. Positional cell type in the epithelium
The original observation of a zone-to-domain topographyetween the OE and the OB has favored the concept that theosition of an OSN in the OE is a critical determinant for itsrojection pattern. Recent re-examinations of the spatial segre-ation of receptor-specific OSN populations revealed that theorsal-to-ventral arrangement of glomeruli targeted by distinctSN populations correlates well with the spatial distributionf the cells along the dorsal to ventral axis in the OE [10,11].n transgenic mouse lines which contain an OR gene placed atn ectopic genomic locus, the transgene-expressing OSNs arerequently positioned at inappropriate locations in the epithe-ium [47,49]. These cells – ectopically located concerning thexpressed OR – did not project to the receptor-specific glomeru-us, but formed novel glomeruli in variable distances from theorrect site. Thus, both the topographic location of a cell and theR-type appears to dictate the projection of an axon.The population of OSNs expressing a given OR can be cate-
orized into two subpopulations: one projecting to a medial, thether to a lateral glomerulus. In gene-targeted mouse lines inhich the target glomeruli for a receptor-specific OSN popula-
ion could be visualized, retrograde tracing experiments demon-trated that the two subpopulations of OSNs were segregatedithin distinct subzones of the OE [50]. It is conceivable that this
ubzonal organization is necessary to confine axons to definedchannels’ on their way to enter the bulb, as a prerequisite foroming in on the correct glomerulus.
.2. Guidepost cells in the cribriform mesenchyme
During development axons of OSNs navigate toward the OBhrough the frontonasal mesenchyme located between the nasalit and the rostral surface of the brain. By embryonic stage
11/12 axons begin to extend from the neuroepithelium andssemble into small fascicles. The navigation of OSN axonshrough the frontonasal mesenchyme appears to be based on
“bridge” formed by so-called ‘migrating cells’ in the mes-
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nchyme [51]. Among those cells in the mesenchyme are pop-lations, which express ORs between E10.25 and E14.0, aniquely high number (∼1200 at stage E13) the receptor typeOR256-17 [52,53]. The OR expressing cells in the cribriformesenchyme also express molecular elements characteristic forSNs, including G�olf, ACIII and OMP. Studies on transgenicMP-GFP mice showed that “extraepithelial” OMP-GFP posi-
ive cells were located in close vicinity to axon bundles, whichroject from the OE to the presumptive OB. Moreover, theseells were primarily located where axons changed directionowards the anterior part of the forebrain. They could thereforeave the function of guideposts for axons approaching the bulb.presorting of axons prior to entering the bulb may direct them
o the correct entry point in the vicinity of their target, thus sig-ificantly reducing the challenge to find the appropriate targetlomerulus.
.3. Influence of the target tissue
Although the axons of OSNs expressing the same OR ulti-ately all project to their common glomerulus, they exit the
pithelium in bundles, which consist of fibers originating fromifferent OSN populations [30,54]. Upon contact with the bulbhese bundles defasciculate and the axons are re-assorted [34].n naturally occurring mutants which do not have an OB, butnstead a fibrocellular mass lacking any cytoarchitecture axonsrom OSNs expressing P2 nevertheless form glomerular-liketructures, despite the absence of normal postsynaptic targets55]. Similar observations were made for bulbectomized mice:utgrowing P2 axons converged, indicating that axonal sortingnd convergence are intrinsic properties of OSN axons. Criti-al cellular elements providing positional information for OSNxons in the OB appear to be the radial glia cells which interactith the axons by their end-feet processes at the earliest stagesf glomerular formation [56].
. Molecular cues
Superimposed on the selective sorting of axons into glomerulire mechanisms that guide axons to defined positions in the OB.ttractive or repulsive interactions apparently drive the growing
xons towards, or away from inappropriate regions of the bulb.SNs appear to be decorated with a great variety of cell surfacearkers, which may contribute to the guidance and recogni-
ion processes of the outgrowing axons [57–60]. However, thenowledge about which of the plethora of surface molecules arenvolved in the guiding process is still limited.
.1. OCAM
The olfactory-specific cell-adhesion molecule (OCAM) ishe only known cell surface molecule which is expressed in aeceptor-defined zone. OCAM expressing cells are confined to
he ventral and lateral region of the OE and accordingly, OCAMositive axons terminate in the corresponding areas of the bulb61]. Elevated expression levels of OCAM in the ventro-lateralegions resulted in wiring errors for P2 expressing OSNs [62].
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verexpression of the transmembrane form of OCAM resultedn convergence of P2 axons close to the correct target glomeruli,hereas overexpression of the GPI-anchored form led to an
ncreased number of P2 axons that bypassed the correct targetnd finally co-converged with axons of other OR identities. Anctopic expression of OCAM in the dorsal zone did not perturbhe regional division of axon projection.
.2. Ephrins
The ephrins and their receptors, the large family of Eph recep-
ors, have also been implicated in the formation of topographic
aps. During embryonic and postnatal stages OSNs expresseveral members of the ephrin-A and -B gene families [63].phrin-A subtypes are differentially expressed in distinct sub-
a(t
ig. 2. OR proteins are present in distinct cellular compartments of OSNs. (A) Immunotrong immunofluorescence is visible in the cilia and knobs of individual OSNs; theB) In the olfactory bulb, receptor proteins can be visualized in axonal processes anxpressing a particular OR are dispersed throughout a distinct area of the olfactory eparts (A) and (B) from [74] with kind permission from the Society for Neuroscience.
velopmental Biology 17 (2006) 402–410
opulations of OSNs and their axons are equipped with differentevels of ephrin-A5 [64]. In mice deficient in ephrin-A3/5 thelomeruli are located at a more posterior position; OSN popula-ions which normally display high ephrin levels show a particu-arly strong shift in their position. Overexpression of ephrin-A5n the other hand results in an anterior shift of glomeruli, indi-ating that the ephrins may participate in determining the axonalermination sites along the anterior–posterior axis [64].
.3. Semaphorins/neuropilins
Another set of molecules which are involved in axon guidancere the semaphorins (sema) and their receptors, the neuropilinsNP). Subsets of NP-1 positive OSNs are distributed throughouthe OE; in wildtype mice their axons avoid the ventral domains
fluorescent visualization of the OR mOR256-17 by receptor-specific antibodies.receptor protein is also present in the soma and axonal process (arrowhead).
d nerve terminals of OSNs converging onto a particular glomerulus. (C) Cellsithelium but converge their axons onto a common receptor-specific glomerulus.
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f the OB where sema3A is expressed [65]. Removal of sema3A,he optimal ligand for NP-1, results in perturbed sorting of axonsnd NP-1 positive axons now also enter the ventral domain ofhe OB [66,67]. NP-2, a co-receptor for the class 3 semaphorinss expressed in a step gradient with highest levels in the lat-ral/ventral regions and lowest in dorsal region of the OE [68]. InP-2 deficient mice the position of glomeruli is hardly affected
69] but axons penetrate into deeper layers of the bulb.
.4. Odorant receptors as axon guidance molecules
Gene targeting experiments which alter the OR codingegions consistently affected glomerular convergence, implying
hat the OR protein itself is involved in axonal guidance. Whenhe coding region for one OR gene was replaced by another,he axons of OSNs expressing the novel OR were redirected to aocation expected for the introduced receptor type [21,25,37,70].
Urrt
ig. 3. Sorting of olfactory axons on their trajectory to the olfactory bulb. (A and B)ascicles (red) from the developing OE traverse the cribriform mesenchyme and progreen) which contact the axonal fascicles by means of their short processes (C). Dorspatially segregated from other axon populations (red). (D) In the OE the axons of OSccording to the topographic area they derive from. When these mixed axon bundles apnd the axons are re-assorted in a receptor-specific manner. Parts (A) and (C) from [7
velopmental Biology 17 (2006) 402–410 407
enetic disruption of an OR gene permits that the affected pop-lation of OSNs can express various other ORs; accordingly, itas found that these cells no longer converge to one glomeru-
us but target multiple glomeruli, apparently directed by theespective novel ORs they express [37,71,72]. Most conceptsonsidering that the OR contributes to the guidance and target-ng of axonal processes imply that the OR protein is present in thexons. Although a critical element in the guidance model, thereas no proof for this idea until very recently. Indirect evidence
ame from a transgenic approach demonstrating that a receptorrotein fused with the fluorescent marker GFP is visible in thexonal termini [37]. A breakthrough was the direct visualiza-ion of the OR protein by receptor-specific antibodies (Fig. 2).
sing these tools, glomeruli of the OB were stained which cor-
esponded to those which are targeted by OSNs expressing theespective OR genes [73,74]. With one set of antibodies, not onlyhe axon terminals in the glomeruli, but also the fibers approach-
During distinct prenatal stages (about E13) bundles of NCAM-positive axonalject towards the forebrain. They pass through an area of OR expressing cellsal to this region (A) axons from mOR256-17 expressing OSNs (green) becomeNs expressing different OR subtypes are grouped together in common bundles,proach the outer nerve layer (ONL) of the olfactory bulb, they are defasciculated5] with kind permission from Springer.
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ng the glomeruli could be visualized [74], suggesting that theR protein is permanently present in the axon, even when therimary targeting event is completed.
The OR proteins are present in the axonal processes alreadyt day E12 [75]. Later, the distal segments of the axons are par-icularly reactive for OR-specific antibodies. One particular OR,
OR256-17, is expressed in a comparatively large number ofells in the developing OE during prenatal stages of mice. Ear-ier than other populations, mOR256-17 axons reach the rostralorebrain and encircle a considerable portion of it. Remark-bly, the area initially targeted by mOR256-17 fibers is ratheridespread and only in the perinatal phase becomes restricted.hether the mOR256-17 cells may represent pioneer OSNs that
pecify regions of the developing OB is still elusive. In the crib-iform mesenchyme, not only the axons of OSNs expressingOR256-17 are immunoreactive, but also the “extraepithelial”OR256-17-expressing cells [75]. This population is intermin-
led within the network of OSN axons. Immunoreactivity isarticularly high on the cell surface and the long protrusions,hich extend along the nerve fascicles. The “extraepithelial”
ells are usually located at bifurcations where small axon fasci-les merge to stronger bundles (Fig. 3). Within these coalescingerves, the axons of receptor-specific OSNs become segregatedrom other axonal populations, suggesting a receptor-specificresorting of OSN axons already in the cribriform mesenchyme.
.5. How does the odorant receptor operate in axonaluidance?
The key question of how the OR may operate in axonal guid-nce has recently been addressed by a series of tremendouslylaborate transgenic approaches in mice. Scrutinizing the ideahat a sequence motif of the OR protein is the important determi-ant, Feinstein and colleagues exploited the fact that a differencef only 11 out of the 309 amino acids is sufficient to target M71nd M72 axons into distinct glomeruli. A series of hybrids inhich M71 was modified with selected M72 residues revealed
ritical amino acids, which re-route axons to novel sites [35].hese residues are distributed throughout the polypeptide chain,ut surprisingly reside predominantly within the transmembraneomains. Some of these receptor variants occur in mouse strainsnd indeed display similar phenotypes. The fact that most of theelevant residues do not reside within extracellular domains ofhe protein and thus may not be accessible for direct homophilicnteractions led to the concept that indirect interactions mediatedy accessory proteins realize the axon-to-axon contact. Consis-ent with the idea that the “sister”-axons recognize each otheria the OR protein, it turned out that not only the type of receptorut also the quantity of protein seems to be important. A signifi-ant difference in level of OR protein resulted in a major shift ofhe glomerular position [35]. In this context it is remarkable thatn unrelated seven-transmembrane receptor, the �2-adrenergiceceptor, could mediate glomerulus formation of an OSN popu-
ation when expressed from an OR gene locus; however, this wasot the case for a V1R receptor [37]. Mutations that drasticallyhange the OR protein features, like truncations or eliminationf the glycosylation site perturb axon outgrowth, suggesting that
usiw
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he OR protein plays a role also in this process. From a series ofene replacement studies it was concluded that the position oflomerulus formation by a given OSN population depends onhich other axon populations are present [35]. These observa-
ions have led to the concept that the site of a receptor-specificlomerulus is not a fixed intrinsic position on the surface of theB but rather that the axons navigate to their presumptive target
egion in a self-organizing process which strongly depends onhe interaction with other axonal populations.
. Conclusion
The precise receptor-topic map of olfactory axon projectionss considered as the basis for the daunting capacity of thelfactory system to accurately process the enormous variety ofdorous stimuli. Novel experimental approaches have consider-bly upgraded our insight not only concerning the principles ofxon convergence but also about the mechanisms determininghe formation and maintenance of the olfactory sensory map.he capability to genetically manipulate the mouse germlineuch that populations of OSNs which express the same OR areelectively labeled, thereby allowing to visualize the trajectoryf their axons has opened new avenues to unravel the patterningf projections; it uncovered a remarkably precise convergencef each receptor-specific axon population to a pair of glomerulin the medial and lateral hemisphere of the bulb. The notion thatRs themselves may directly be involved in axonal pathfinding
nd targeting was supported by the discovery that the OR proteins in fact present in axonal processes and endings; however,n understanding of the mechanisms by which it contributes tohe complex topographical rearrangements of the axonal fibersn the process of glomerulus formation is still elusive. But no
atter whether the OR proteins recognize chemoattractive cuesr establish homophilic interactions, they will operate in concertith a variety of canonical cell surface molecules to first arrange
xons into intermixed bundles which upon contact with the bulbefasciculate; then axons are re-assorted into receptor-specificundles which converge into distinct glomeruli. The complexrocesses of axon navigation, fiber sorting and cell recognitionre supposed to be governed by a hierarchical system of recog-ition and adhesion molecules. Although the primary processesf glomerulus formation appear to be mainly based on molec-lar determinants, recent evidence indicates that the postnatalefinement of the olfactory projections relies on sensory activity.
Whereas in the visual, auditory and somatosensory systemsprecise point-to-point topographic map is essential for a
epresentation of the sensory information, for the olfactoryystem it is currently unclear whether the characteristicopography of glomeruli across the surface of the bulb mayave immediate functional implications for the processing oflfactory information.
Although considerable and partially unpredictable progressas been made in understanding the principles and mechanisms
nderlying the formation and maintenance of the olfactory sen-ory map, many fundamental issues remain open, including thedentification of relevant guidance molecules and their interplayith the OR proteins in establishing the olfactory sensory map.
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urther conceptual advances and their rigorous experimentalcrutiny will be necessary to unravel more of the secrets underly-ng the design and the operation of the olfactory sensory system.
cknowledgement
The work from this laboratory was supported by the Deutscheorschungsgemeinschaft.
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