1 Laboratory for Neurobiology of Synapse, RIKEN Brain Science Institute,
Wako-shi, Saitama 351-0198, Japan
2 Mitsubishi Kagaku Institute of Life Sciences, Machida-shi, Tokyo 194-8511,
Japan
Authors for correspondence (e-mail:
yoshihara{at}brain.riken.go.jp
or
kitamura{at}ncnp.go.jp)
Accepted 15 December 2004
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SUMMARY |
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Key words: Arx, Olfactory bulb, Granule cells, Periglomerular cells, Rostral migratory stream, Radial glia, Olfactory axons, Axon guidance, Fibrocellular mass, Mouse
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Introduction |
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The OB is the first relay station in the olfactory system, where odor
information is transferred from the periphery to higher centers in the brain
(Mori et al., 1999). It
comprises limited types of neurons and glia with a simple layer organization.
Outermost is the olfactory nerve layer (ONL) consisting of olfactory axons
projecting from the olfactory epithelium (OE) and olfactory ensheathing glia
that enwrap these axons. Beneath the ONL lies the glomerular layer (GL) where
olfactory axons make synapses in glomeruli with primary dendrites of
projection neurons and dendrites of interneurons. Projection neurons in the OB
are mitral and tufted cells whose cell bodies are situated in the mitral cell
layer (MCL) and the external plexiform layer, respectively. In addition, the
external plexiform layer contains secondary dendrites of mitral and tufted
cells that make dendrodendritic synapses with spines of granule cells. Local
interneurons in the OB are classified into two major types: periglomerular
cells and granule cells. Somata of periglomerular cells are localized around
glomeruli, while those of granule cells are mostly found in the granule cell
layer (GCL).
OB projection neurons and interneurons are destined in different ways. The
projection neurons are born earlier than the interneurons
(Hinds, 1968). This time
difference of neurogenesis results in two steps of OB morphogenesis: the first
step as a slight evagination of primordial OB at the anterior tip of the
telencephalon by accumulation of differentiated projection neurons [embryonic
day 12-13 (E12-13) in mice] and the second step as a further expansion by
massive addition of differentiated interneurons (E14-18 in mice). In addition,
the most striking difference is that the interneurons are continuously
generated throughout the animal's life. Their progenitors are born in the
subventricular zone (SVZ) of the cerebral cortex and migrate toward the OB via
the rostral migratory stream (RMS)
(Luskin, 1998
).
Here, we analyzed olfactory system development in Arx-deficient mice. Arx mutation resulted in the impaired entry of interneuron progenitors into the OB and the disruption of OB layer organization. In addition, most of the olfactory axons failed to reach the OB and formed a tangle-like structure between the OE and OB, although Arx is not expressed in the olfactory sensory neurons. These observations suggest that Arx is essential for development of the olfactory system and that the proper projection of olfactory axons depends on the normal development of the OB.
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Materials and methods |
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Production of polyclonal antibodies against Tbx21
In the brain, a T-box transcription factor, Tbx21, is specifically
expressed in mitral/tufted cells (Faedo et
al., 2002). To obtain a good immunohistochemical marker, we
generated polyclonal antibodies against Tbx21. A peptide corresponding to the
carboxyl-terminal 20 amino acids (GAPSPFDKETEGQFYNYFPN) of mouse Tbx21 was
synthesized, coupled to keyhole limpet hemocyanin, and used to immunize
rabbits and guinea pigs. The antisera showed specific labeling of the
mitral/tufted cells.
Histology and immunohistochemistry
Nissl staining was performed as described previously
(Long et al., 2003). Images
were obtained with an upright light microscope equipped with a cooled CCD
digital camera (Olympus AX80, DP50).
Immunohistochemistry was performed essentially as described previously
(Yoshihara et al., 1997).
Sections were blocked with PBS containing 10% normal horse serum, incubated
with primary antibodies overnight at 4°C, washed, and incubated with Cy3-,
Cy5-(Jackson ImmunoResearch Laboratories) or Alexa488-(Molecular Probes)
labeled secondary antibodies. All secondary antibodies were used at 1:300
dilution. Antigen retrieval pretreatment with a microwave oven (550 W, 5
minutes) greatly enhanced the immunoreactivity of Arx protein. The following
primary antibodies were used: Arx (rabbit, 1:1000)
(Kitamura et al., 2002
), DCC
(goat, 1:100; Santa Cruz Biotechnology), Eph-A4 (goat, 1:100; R&D
Systems), Eph-B1 (goat, 1:50, R&D Systems), Eph-B2 (goat, 1:50, R&D
Systems), Eph-B3 (goat, 1:50, R&D Systems), ephrin-B2 (goat, 1:50, R&D
Systems), ephrin-B3 (goat, 1:50, R&D Systems), GABA (rabbit, 1:2000;
Sigma) (rat, 1:400; Affiniti Research Products), GLAST (guinea pig, 1:8000;
Chemicon),
1 integrin (rabbit, 1:1000; Chemicon), ß1 integrin
(rat, 1:50; BD Pharmingen), ß8 integrin (goat, 1:100; Santa Cruz
Biotechnology), L1 (rat, 1:200; Chemicon), LacZ (rabbit, 1:300; 5Prime 3Prime
Inc.), NCAM (rat, 1:500; Chemicon), neuropeptide Y (rabbit, 1:3000; Incstar),
neuropilin-1 (goat, 1:200; R&D Systems), neuropilin-2 (goat, 1:200;
R&D Systems), OCAM (rabbit, 1:1000)
(Yoshihara et al., 1997
),
olfactory marker protein (OMP) (goat, 1:20000; provided by F. Margolis)
(Keller and Margolis, 1975
),
PSA-NCAM (mouse, 1:500; provided by T. Seki),
(Seki and Arai, 1993
), Rig1
(rabbit, 1:1500), Robo1 (rabbit, 1:1500), Robo2 (rabbit, 1:1500) (anti-Rig1,
-Robo1, -Robo2 antibodies were provided by F. Murakami and A. Tamada)
(Sabatier et al., 2004
),
Reelin (CR-50) (mouse, 1:200; provided by M. Ogawa)
(Ogawa et al., 1995
) S100
(rabbit, 1:5000; Dako), Tbx21 (rabbit, 1:10000; guinea pig, 1:25000), Thy-1
(rat, 1:200; Santa Cruz Biotechnology), tyrosine hydroxylase (TH) (mouse,
1:200; Chemicon). Images of immunofluorescently labeled sections were obtained
with a fluorescent microscope (Zeiss AxioPlan2) equipped with a cooled CCD
camera (Olympus DP70) or confocal laser scanning microscopes (BioRad
MicroRadiance and Leica TCS SP2). All images were analyzed with Adobe
Photoshop 6.0 software (Adobe Systems).
In situ hybridization
In situ hybridization was performed using digoxigenin (DIG)-labeled cRNA
probes as described previously (Tsuboi et
al., 1999). The following probes were used: Dlx2
(nucleotides 317-1051, GenBank NM_010054), Dlx5 (nucleotides 211-959,
GenBank NM_010056), and Nurr1 probe (nucleotides 340-1147, GenBank
S53744). These probes were obtained by RT-PCR from brain RNA of newborn mice.
Hybridization signals were detected with alkaline phosphatase-conjugated
anti-DIG Fab fragments (1:1000; Roche Applied Science), followed by color
development with NBT and BCIP (Roche Applied Science). All images were
captured with a cooled CCD camera (Olympus DP50) on a light microscope
(Olympus AX80).
BrdU labeling
BrdU labeling was performed as described previously
(Kitamura et al., 2002).
Pregnant mice were injected intraperitoneally with BrdU (40 mg/kg) and killed
either after 1 hour or at P0. For proliferation analysis, 10 µm serial
coronal sections were prepared form the anterior tip of the OB to the medial
ganglionic eminence of E14.5 wild-type and mutant mice, and stained with
anti-BrdU antibody (rat, 1:50; Oxford Biotechnology). BrdU(+) cells in every
ten sections were counted (n=3 for each genotype).
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Results |
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There are two major types of GABAergic interneurons in the OB:
periglomerular cells and granule cells. In addition, a subpopulation of
periglomerular cells also expresses catecholamine-synthesizing enzyme, TH
(Kosaka et al., 1995). Arx
immunoreactivity markedly overlapped with GABA(+) profiles in both the GL and
GCL (Fig. 1K-V). In the GL,
colocalization of Arx, GABA, and TH was observed, and the TH(+) periglomerular
cells were always positive for Arx and GABA
(Fig. 1K-R, arrowheads). In the
GCL, a significant population of cells was positive only for Arx, but not
GABA, probably corresponding to immature GCs
(Fig. 1K-N,S-V).
Glutamate transporter GLAST is expressed in radial glia
(Hartfuss et al., 2001). A
weak but significant expression of Arx was detected in GLAST(+) radial glia
(Fig. 1S-V, arrowheads). These
results demonstrate that Arx is strongly expressed in the GABA(+) and TH(+)
local interneurons and weakly in the GLAST(+) radial glia, but not in the
Tbx21(+) projection neurons, in developing OB.
Failure of OB morphogenesis in Arx-deficient mice
We previously noticed that Arx-deficient mice had a smaller OB
than wild-type mice (Kitamura et al.,
2002). Here we made extensive analyses on abnormalities in the
olfactory system caused by mutation of the Arx gene. First, we
examined gross morphology of the developing OB. At E12.5, no apparent
difference was observed in the telencephalic structure between wild-type
(Fig. 2A) and
Arx-deficient mice (Fig.
2B). At E16.5, the formation of the OB was evident as a protrusion
from the anterior tip of telencephalon in wild-type mice
(Fig. 2C). In contrast, only a
slight protrusion of presumptive OB was detectable in mutant mice
(Fig. 2D). At P0, the OB of the
mutant mouse (Fig. 2F) was much
smaller than that of wild-type mice (Fig.
2E). In addition, there was a wide empty space between the right
and left OB of mutant mice (Fig.
2D,F, asterisks). Thus, Arx mutation severely impairs OB
morphogenesis.
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To visualize the migration process of OB interneuron progenitors more clearly, we performed another BrdU labeling experiment. Pregnant mice received an injection of BrdU at E14.5 or E16.5 to label cells of different birth dates. In newborn mice (P0), BrdU-labeled cells were examined for their location along the migratory pathway of OB interneuron progenitors. In wild-type mice, numerous BrdU-labeled OB interneurons born at E14.5 were dispersed throughout GCL (Fig. S2A in the supplementary material), while younger interneurons and their progenitors born at E16.5 were more densely packed in the core region of the GCL and in the RMS (Fig. S2C in the supplementary material). In contrast, although the migration of interneuron progenitors in Arx-deficient mice was observed within the RMS, they stalled at the rostral tip of the RMS without entering into the OB (Fig. S2B,D in the supplementary material). These results suggest that Arx mutation affects the entry of interneuron progenitors into the OB, rather than the migration process within the RMS.
We asked whether the impaired entry of interneuron progenitors into the OB is cell-autonomous or non-cell-autonomous by analyzing Arx heterozygous female mice. Because the Arx gene is located on the X chromosome, Arx heterozygous female mice possess both Arx-expressing cells and Arx-deficient cells in a mosaic fashion. Arx-deficient cells can be detected by expression of ß-galactosidase. The OB of Arx heterozygous female mice appeared normal with respect to the layer organization and olfactory axonal projection (data not shown). However, ß-galactosidase-positive Arx-deficient interneuron progenitors were located only within the RMS and failed to enter the OB (Fig. 4O). This result indicates the impaired entry of Arx-deficient interneuron progenitors into the OB is cell-autonomous.
Loss of TH-positive interneurons in Arx-deficient mice
As shown above (Fig. 1K-R),
TH is expressed by a subpopulation of the GABAergic periglomerular cells
(Kosaka et al., 1995). We
asked whether the Arx mutation influences development of TH(+)
periglomerular cells. In wild-type mice, TH was expressed in Arx(+)/GABA(+) OB
periglomerular cells and in Arx() midbrain dopaminergic neurons at
E16.5 and P0 (Fig. 5A,C,E,G,I).
In Arx-deficient mice, TH immunoreactivity was completely absent in
OB and RMS (Fig. 5B,F,J),
although GABA(+) cells were observed (Fig.
5H,J). On the other hand, TH(+) neurons were normally present in
the substantia nigra of mutant mice (Fig.
5D). In addition, Nurr1, an orphan nuclear receptor
expressed in TH(+) periglomerular cells in wild-type mice
(Fig. 5K)
(Backman et al., 1999
;
Liu and Baker, 1999
), was not
detected in Arx-deficient OB (Fig.
5L). These results indicate that Arx is required for the
differentiation of TH(+) periglomerular cells.
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The morphology of mitral cells was examined by triple fluorescent labeling
with three antibodies: anti-Thy-1 (Fig.
6I,J,O,P, whole dendrite labeling)
(Xue et al., 1990),
anti-Reelin (Fig. 6K,L,O,P,
proximal dendrite labeling) (Long et al.,
2003
), and anti-Tbx21 (Fig.
6M-P, cell body labeling). In wild-type mice, all mitral cells
projected their dendrites regularly and consistently toward the apical
direction (Fig. 6I,K,M,O). In
contrast, the orientation of proximal dendrites of mitral cells was variable
in Arx-deficient mice (Fig.
6L,P), while distal dendrites normally located in the apical
portion of the OB (Fig. 6J,P).
In addition, Thy-1 immunoreactivity in the proximal dendrites was absent in
mutant mice (Fig. 6J,P). These
results suggest that Arx mutation causes disorganization of the
MCL.
Abnormal projection of olfactory axons in Arx-deficient mice
We next asked whether the disorganized OB structure might affect axonal
projection of the olfactory sensory neurons from the OE to the OB. At E12.5,
olfactory pioneer axons first reached the OB anlagen at the anterior tip of
the telencephalon in both wild-type and Arx-deficient mice
(Fig. 7A,B). At E16.5, no
difference was observed with respect to the gross morphology of the OE and the
differentiation of OMP-positive sensory neurons between wild-type and mutant
mice (Fig. 7C-F). However,
there was a clear difference in the trajectory of olfactory axons at E16.5. In
wild-type mice, all olfactory axons reached and surrounded OB to form ONL
(Fig. 7G). In contrast, most of
the olfactory axons in mutant mice failed to reach the OB and formed a large
tangled sphere between the OE and OB (Fig.
7H, asterisk), a structure called the `fibrocellular mass' (FCM)
first identified in naturally occurring mutant mouse extratoes
(Xt/Xt) (St John et al.,
2003). Only a small fraction of olfactory axons was in direct
contact with the surface of the OB (Fig.
7H, arrowheads).
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Neuropilin-1 and -2 are cell surface receptors for chemorepellents of
semaphorin family molecules (Raper,
2000). Neuropilin-1 is expressed in a subset of olfactory axons
that terminate in two unique symmetrical domains in the medial and lateral
hemispheres of the OB (two yellow regions in
Fig. 8S)
(Nagao et al., 2000
). In the
FCM of Arx-deficient mice, a segregation of neuropilin-1(+) and
() axons was clearly observed with a sharp boundary
(Fig. 8T, asterisk). Manners of
segregation were different between OCAM and neuropilin-1
(Fig. 8R,T, asterisks).
Neuropilin-2 is expressed in a small subset of olfactory axons that terminate
in the most anteromedial region and most posterior region of the OB (yellow
regions in Fig. 8U)
(Norlin et al., 2001
). In
mutant mice, neuropilin-2(+) axons were observed in small regions at the edge
of the FCM, while neuropilin-2() axons occupied the central portion of
the FCM (Fig. 8V, asterisk).
Thus, olfactory axons showed clear segregation that can be defined by
differential expression of the cell recognition molecules in the FCM. This
result suggests that the segregation of olfactory axons is independent of the
direct contact with target OB.
As mentioned above (Fig.
8H), a small subset of olfactory axons could reach the
anteromedial surface of the OB in Arx-deficient mice. These axons
were positive for OCAM and neuropilin-2, but negative for neuropilin-1
(arrowheads in Fig. 8R,T,V). In
wild-type OB, the anteromedial cluster of
OCAM(+)/neuropilin-1()/neuropilin-2(+) glomeruli was called `a
tongue-shaped area' (arrowheads in Fig.
8Q,S,U) (Nagao et al.,
2000). From the topographical location and molecular expression,
the OB region innervated by these olfactory axons in Arx-deficient
mice may correspond to the tongue-shaped area in the wild-type mice.
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Discussion |
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Although the expression of GABA was observed in Arx-deficient
mice, a TH(+) subpopulation of GABAergic interneurons was completely absent in
the OB. Moreover, the OB of mutant mice lacked expression of Nurr1, a
putative transcription factor regulating differentiation of TH(+) OB
interneurons (Backman et al.,
1999; Liu and Baker,
1999
). These results indicate that Arx mutation affects
differentiation of a specific type of OB interneurons. A plausible explanation
for this phenotype would be that the Arx gene may be located upstream
of Nurr1 and TH genes in a genetic cascade for the
differentiation. However, we cannot exclude a possibility that the progenitors
of TH(+) OB interneurons may not be exposed to appropriate differentiation
signals produced in the OB due to the impaired entry into the OB.
Although Arx is not expressed in mitral cells, disorganization of the MCL
was observed as a thicker and irregular contour. Since massive addition of
interneurons from the RMS results in the expansion of the OB at late embryonic
stages, we assume that the disorganization of the MCL in
Arx-deficient mice is caused by the decrease of the GCL resulting
from the impaired entry of interneurons into the OB. Another possibility is
that Arx may be expressed in progenitors of OB projection neurons. Recently,
it was reported that radial glia are progenitors for the majority of neurons
in the brain (Anthony et al.,
2004). If it is also the case for OB projection neurons, the
abnormal layering of OB projection neurons may be attributable to a
cell-autonomous defect caused by Arx mutation in radial glia.
Alternatively, putative signal(s) may be missing in Arx-deficient
mice, which is produced by OB interneurons, radial glia, or olfactory sensory
neurons and directs normal layering of OB projection neurons.
A non-cell-autonomous defect was seen in the projection pattern of olfactory sensory neurons. In Arx-deficient mice, most of the olfactory axons failed to reach the OB and terminated in a tangled structure, the FCM, in front of the OB (discussed below).
Transcription factors regulating development of OB interneurons
Three members of the Dlx transcription factor family (Dlx-1, -2,
-5) have been proposed to play crucial roles in development of the
olfactory system. They are expressed in the OB interneurons and their
progenitors with consecutively differential but overlapping patterns
(Bulfone et al., 1998;
Levi et al., 2003
;
Long et al., 2003
). The
Dlx-1 and Dlx-2 double knockout mice show the most severe
defects in the proliferation and migration of the OB interneurons: they are
completely absent (Bulfone et al.,
1998
). In contrast, the phenotypes of Dlx-5-deficient
mice are milder and, to some extent, similar to those of the
Arx-deficient mice, including (a) size reduction of the OB, (b)
impaired migration of OB interneurons, (c) the disorganization of the MCL, and
(d) impaired axonal projection of olfactory sensory neurons forming the FCM.
Unlike Arx, however, Dlx-5 is also expressed in the
olfactory sensory neurons and its mutation causes a drastically reduced
proliferation, raising a possibility that some of the above-mentiond
phenotypes may be attributable to abnormality in the sensory neurons
(Levi et al., 2003
;
Long et al., 2003
). Because we
detected the expression of Dlx-2 and Dlx-5 in the
Arx-deficient mice, the Arx gene may play roles in a genetic
cascade different from the Dlx cascade, or downstream of Dlx
genes. Analysis of Arx expression in the Dlx-5-deficient
mice would provide an answer to this issue.
Bidirectional interactions between OE and OB during development
A possibility of mutual influences between the OE and OB on inductive and
developmental processes has been proposed and extensively studied (for a
review, see López-Mascaraque and de
Castro, 2002). In Xenopus, the surgical ablation of
olfactory placode results in loss or hypoplasia of the OB
(Stout and Graziadei, 1980
;
Graziadei and Monti-Graziadei,
1992
; Byrd and Burd,
1993
). In rats, the arrival of pioneer olfactory axons regulates
the cell cycle kinetics and the rate of differentiation of neuronal
progenitors to induce the formation of the OB
(Gong and Shipley, 1995
). In
mice deficient of the olfactory cyclic nucleotide-gated channel specifically
expressed in olfactory sensory neurons, the OB is smaller than in wild-type
mice (Lin et al., 2000
). These
studies suggest that the OE somehow influences the development of the OB.
Then, how about the influence in an opposite direction: from the OB to the
OE? This possibility was studied mainly using the Gli3 mutant mice,
extratoes. The OB is completely absent in Gli3-deficient
mice and OB projection neurons distributed sparsely on the surface of
rostrolateral forebrain undergo apoptosis
(Hui and Joyner, 1993;
St John et al., 2003
). On the
other hand, OE development proceeds normally in respect of its gross
morphology and expression of signal transduction molecules including odorant
receptors (Sullivan et al.,
1995
). However, olfactory axons do not reach the telencephalon and
instead terminate in the abnormal structure called the FCM
(St John et al., 2003
). Thus,
the OB appears not to influence the cellular proliferation and differentiation
of the OE, but may have an instructive role in guidance of the olfactory
axons. In Arx-deficient mice, only a small population of olfactory
axons made contact with the OB, but most of them failed to reach the OB and
terminated in the FCM. Because Arx is not expressed in the olfactory sensory
neurons, we assume that Arx regulates the expression of putative instructive
signal(s) produced in the OB for proper innervation of olfactory axons.
Although the identity of such signal(s) is unknown yet, we speculate that it
may be produced in OB radial glia for the following reasons. (1) Olfactory
axons innervate the OB normally in Dlx1/Dlx2 double mutant mice that
lack OB interneurons (Bulfone et al.,
1998
). Therefore, the involvement of OB interneurons is excluded.
(2) Olfactory axons innervate the OB normally in Tbr1 mutant mice
that lack OB projection neurons (Bulfone et
al., 1998
), eliminating the involvement of OB projection neurons.
(3) Arx is expressed only in radial glia and interneurons of the OB,
but not in other types of cells in the olfactory system. Its mutation causes
the failure of olfactory axon projection. (4) Development of OB radial glia
closely correlates with the projection of olfactory axons and formation of
glomeruli (Bailey et al., 1999
;
Puche and Shipley, 2001
).
Further investigation is necessary to clarify the identity and origin of this
putative instructive signal(s) in the developing olfactory system.
In Arx-deficient mice at P0, a small subset of olfactory axons
kept contact with the rostromedial region of the OB and were positive for OCAM
and neuropilin-2, but negative for neuropilin-1, reminiscent of the
tongue-shaped area of the OB in wild-type mice
(Nagao et al., 2000). Our
analysis revealed that the pioneer olfactory axons could reach the anterior
tip of the telencephalon in both wild-type and Arx-deficient mice at
E12.5 (Fig. 7A,B). These
earliest growing axons were also positive for OCAM and neuropilin-2, but
negative for neuropilin-1 (data not shown). Thus, a subset of olfactory axons
reaching mutant OB at E16.5 (Fig.
7H) and P0 (Fig. 8)
appears to be a remnant of the pioneer axons. If so, a target region
innervated by pioneer axons becomes the future `tongue-shaped area' in the OB.
Thus, Arx-deficient mice provide an important clue for a likely
relationship between the innervation of pioneer olfactory axons at early
developmental stages and the formation of the `tongue-shaped area' in the
glomerular map of adult OB. Furthermore, based on this assumption, the
olfactory axons that fail to contact mutant OB may be derived from the
`follower' olfactory axons, but not from the `pioneer' axons. We speculate
that Arx regulates the expression of putative instructive signal(s) produced
in the OB for proper innervation of the `follower' axons, but not the
`pioneer' axons.
Interestingly, olfactory axons in the FCM of Arx-deficient mice
are clearly segregated with respect to the expression of cell recognition
molecules (Fig. 8R,T,V). This
result indicates that the segregation of different subsets of olfactory axons
takes place even without direct contact with the OB. This notion is supported
by a previous report describing that, in Gli3 mutant mice, the
olfactory axons originating from the sensory neurons expressing an odorant
receptor P2 are able to sort out from other axons and converge to specific
loci in the FCM (St John et al.,
2003). This phenomenon may be achieved by using intrinsic
machineries equipped in the olfactory axons. Alternatively, there may be an
influence from other cells in the environment such as the olfactory
ensheathing glia that have been reported to play an important role in
olfactory axon sorting in developing moth Manduca sexta
(Oland et al., 1998
;
Higgins et al., 2002
).
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/4/751/DC1
* Present address: Department of Mental Retardation and Birth Defect
Research, National Institute of Neuroscience, National Center of Neurology and
Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
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