Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
A Model for Axon Navigation Based on Glycocodes in the Primary Olfactory System
1 Department of Anatomy & Developmental Biology, School of Biomedical Sciences, University of Queensland, Brisbane 4072, Australia and 2 Centre for Functional and Applied Genomics, Institute of Molecular Biosciences, University of Queensland, Brisbane 4072, Australia
Correspondence should be sent to: Brian Key, e-mail: brian.key{at}uq.edu.au
Key words: carbohydrate, fasciculation, growth cone, guidance, lectin, olfaction
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Introduction |
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 Top Introduction Role of sorting and...ConclusionSummaryReferences |
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In rodents, primary olfactory sensory neurons reside in the psuedostratified olfactory neuroepithelium lining the caudal nasal cavity. Each neuron expresses a single odorant receptor and all neurons expressing the same receptor are typically located in one of four bands of neuroepithelium lining the nasal cavity (Buck and Axel, 1991
;
Vassar et al., 1993, 1994).
While there are ~1000 different odorant receptor genes, there are probably many more
distinct subpopulations of sensory neurons due to regional differences in the nasal
cavity of expression of cell surface carbohydrates (Key and Akeson, 1993;
Puche and Key, 1996;
Dowsing et al., 1997;
St John and Key, 2001;
Storan et al., 2004) and
putative cell adhesion molecules such as OCAM (Yoshihara et al., 1997). The differential
expression of odorant receptors does more than just provide a large repertoire of sensory
receptors for the detection of odors. These molecules have been shown to play a major
axon guidance role (Mombaerts et al.,
1996). All primary olfactory neurons expressing the same odorant receptor
protein project axons to the olfactory bulb where they converge and typically form two
synaptic glomeruli with the dendrites of second-order olfactory neurons and interneurons.
While this projection pattern in itself is not unique it is the fact that these glomeruli
are positioned in topographically fixed positions in the bulb that creates a complex
navigational problem for growth cones. In the retinotecal pathway, retinal neurons project topographically from the retina on to the tectum in a point-to-point map. The maintenance of near-neighbor relations between the sense organ and the target allows the use of complementary gradients of chemorepulsive receptors and ligands to simply determine the topography. This is not the case in the primary olfactory system since the mosaic and stochastic expression of odorant receptors in the olfactory neuroepithelium negates the use of any simple matching gradient of ligand in the bulb. Moreover, it requires that the axons of highly dispersed neurons must sort out and converge on to defined points in space in the bulb at positions which have little spatial correlation to the position of parent neurons in the nasal cavity. Mechanisms are needed to sort about 1000 different subpopulations of axons to enable them to converge and form glomeruli.
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Role of sorting and selective fasciculation in axon guidance |
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TopIntroductionRole of sorting and...ConclusionSummaryReferences |
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Examination of axons expressing the P2 odorant receptor during the earliest stages of glomerular formation revealed that these axons do not selectively fasciculate (Royal and Key, 1999
). Thus, the initial sorting
out of axons expressing one particular receptor from those axons expressing other
receptors must not be via selective adhesion mediated by odorant receptors. A clue to the
putative basis of this sorting came from observations of the behavior of axons expressing
specific cell surface carbohydrates recognized by the plant lectin Dolichos
biflorus agglutinin (DBA) (Key and Akeson,
1993). These axons arise from neurons widely dispersed through the dorsal
lateral nasal cavity of the mouse and they course within mixed nerve fiber fascicles as
they project to the olfactory bulb. There is no evidence of selective fasciculation of
these axons into bundles exclusively containing this subpopulation of axons within the
peripheral nerve fascicles. However, at the level of the olfactory bulb there is a
radical change in the trajectory of these axons. As they enter the outer nerve fiber
layer these axons begin to sort out from other axons and self fasciculate into discrete
bundles. These bundles of DBA stained axons then innervate numerous
mosaically-distributed glomeruli particularly in the dorsocaudal olfactory bulb.
This sorting behavior is not peculiar to these axons since it has also been shown
that axons expressing different levels of lactosamine containing carbohydrates also sort
out as they enter the bulb (Puche and Key,
1996). Large fascicles of axons are present that contain low, medium and high
levels of these sugars and these sorted axon bundles innervate glomeruli exhibiting
similar levels of these lactosamine sugars. Lactosamine has recently been shown to be
selectively present in unique glycoforms of the neural cell adhesion molecule NCAM which
mediate olfactory axon fasciculation in vitro (Storan et al., 2004). It appears that sugars such
as lactosamine may be responsible for the sorting of axons into large bundles while DBA
ligands may further subdivide these fascicles into smaller discrete fascicles. Thus, as
axons course through the nerve fiber layer they begin to become progressively sorted into
smaller and smaller fascicles on the basis of the expression of cell surface
carbohydrates. These sugars can be considered as providing a cell surface signature or
‘glycocode’ that allows axons to be sorted prior to their convergence on
glomerular targets. Most likely this self-fasciculation, mediated by carbohydrates, is a
necessary prerequisite for the targeting of axons to specific glomerular sites in the
olfactory bulb, based on expression of odorant receptor.
It is envisaged that axons expressing lactosamine consist of subpopulations of axons
expressing many different odorant receptors. For instance, some of these axons may
express the P2 odorant receptor and thus lactosamine may provide one mechanism for
sorting these axons within a hierarchy of different glycocodes. Axons within these
lactosamine bundles may also express DBA ligands which in turn express a smaller
repertoire of odorant receptors. There may be several reiterations of this sorting into
fascicles of smaller and smaller size coded by the expression of discrete cell surface
carbohydrates (St John and Key, 2001).
However, it is unlikely that axons expressing a single odorant receptor express an
entirely unique glycode not shared by other receptor subpopulations since, as noted
above, axons expressing the same odorant receptor never self-fasciculate en route to
their target (Royal and Key, 1999). It
appears that axons expressing P2 odorant receptors fasciculate with other axons
expressing different receptors but sharing the same cell surface carbohydrates as they
approach their prospective glomerular targets. P2 axons probably defasciculate from these
small fascicles in response to other guidance cues in the target zone. With subsequent
development, as more and more P2 axons grow into the bulb, some of these dispersed P2
axons form small distinct fascicles that enter the glomerulus in random approach
patterns, as is observed in mature glomeruli (Royal and Key, 1999).
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Conclusion |
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TopIntroductionRole of sorting and...ConclusionSummaryReferences |
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Glycocodes are not the only mechanism sorting axons (Key and St John, 2002
;
St John et al., 2002). Most
likely molecules such as NCAM-180 (Treloar et
al., 1997), OCAM (Yoshihara
et al., 1997) and Neuropilin-1 (Crandall et al., 2000;
Taniguchi et al., 2003),
which are expressed by large subpopulations of axons that course in like bundles to the
olfactory bulb, are also mediating sorting and selective fasciculation. There is probably
a hierarchy of multiple cues that are responsible for guiding axons to the vicinity of
their target where local guidance cues then become dominant. The role of timing of axon
growth into the bulb should also be considered in models of axon navigation in the
olfactory system. The behavior of axons such as selective sorting is clearly dependent on
the environmental context in which the axons are growing, which varies with time of
outgrowth of axons to the bulb. We have not dealt here with the possible mechanisms
responsible for the fasciculation of axons expressing the same cell surface glycocodes;
however, it is likely that receptors such as the galectin family of carbohydrate binding
proteins are involved in this behavior (Storan
et al., 2004). |
Summary |
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TopIntroductionRole of sorting and...ConclusionSummaryReferences |
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A major question in developmental neurobiology concerns understanding the molecular and cellular mechanisms underlying axon growth and guidance in the developing nervous system. Deciphering the complex interplay of molecular signals responsible for establishing axon and nerve pathways is essential for any effective therapeutic approach to regeneration and repair of injured nervous systems. While many molecules have been shown both in vitro and in vivo to participate in growth cone navigation there is no pathway in the mammalian nervous system for which we understand the principal mechanisms driving the establishment of axon pathways from neuron of origin to target cell. The primary olfactory system is one region that demands particular attention due to it peculiar regenerative capacity. It is the only region in the mammalian nervous system that exhibits continual neuronal turnover and axon growth and guidance throughout embryonic development as well as adult life. Understanding the unique characteristics of axon navigation in this system should provide insight into why the rest of the nervous system is so refractory to regeneration and repair. We present here a model for axon navigation based on the use of cell surface glycocodes for the sorting and selective fasciculation of primary olfactory axons in the nerve fiber layer of the olfactory bulb.
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References |
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TopIntroductionRole of sorting and...ConclusionSummaryReferences |
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