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First published online 26 January 2006
doi: 10.1242/dev.02257
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1 Division of Brain Function, National Institute of Genetics, Graduate
University for Advanced Studies (SOKENDAI), Yata 1111, Mishima 411-8540,
Japan.
2 PREST, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama,
Japan.
* Author for correspondence (e-mail: tathirat{at}lab.nig.ac.jp)
Accepted 16 December 2005
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SUMMARY |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Key words: Netrin 1, Ventral tangential migration, Lateral olfactory tract, Guidepost neuron, Lot cells, Mouse
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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). Among the various modes of migration, recent studies have
emphasized the roles of tangential migration in the supply of constituent
neurons to their distant targets (Marin
and Rubenstein, 2003). For example, the majority of cortical
GABAergic interneurons originates from the ventral telencephalon and is
supplied to the neocortex through dorsal tangential migration
(O'Rourke et al., 1992;
de Carlos et al., 1996;
Tamamaki et al., 1997;
Anderson et al., 1997;
Anderson et al., 2001;
Wichterle et al., 2001;
Jimenez et al., 2002). Given
that these neurons are essential for cortical function, this migration is
considered to be precisely controlled during development by multiple guidance
molecules (Marin and Rubenstein,
2003).
We discovered a unique ventral tangential migration stream of
early-generated neurons in the mouse telencephalon
(Sato et al., 1998). These
neurons, designated as lot cells, are characterized by staining with the
monoclonal antibody (mAb) lot1, and serve a specific function as guideposts
for olfactory bulb axons into the lateral olfactory tract (LOT)
(Sato et al., 1998). Although
lot cells specifically populate the LOT area during the guiding process, the
cells originate from the widespread area of the neocortex in an earlier
developmental stage and subsequently migrate ventrally and tangentially
towards the future LOT area, which is located on the boundary between the
neocortex and the ganglionic eminence (GE)
(Tomioka et al., 2000). In the
LOT area, lot cells terminate their ventral tangential migration, abruptly
changing their orientation from the dorsoventral to rostrocaudal axis, and
assemble into a compact cellular array
(Tomioka et al., 2000), which
thereafter serves as the scaffold of growing olfactory bulb axons. A similar
neuronal migration is observed in the telencephalon of chick embryos
(Striedter et al., 1998),
suggesting evolutionary conservation of this tangential migration stream.
Nevertheless, the precise mechanism of this migration remains to be
elucidated.
The present study is aimed at determining the mechanisms that regulate the
ventral tangential migration in the developing telencephalon. We reproduced
this migration in an organotypic culture system, and found that signals in the
neocortex direct lot cells ventrally, while other mechanisms exclude lot cells
from the GE. The screening for candidate modifiers in the migration identified
netrin 1, a prominent axon guidance molecule
(Kennedy et al., 1994;
Serafini et al., 1994), as an
attractant for lot cells. In mice mutant for genes encoding netrin 1 and its
functional receptor Dcc, lot cells were not appropriately distributed in the
LOT area and there was a slight but specific disruption in the projection of
olfactory bulb axons. The results indicate that netrin 1 regulates the
migration of lot cells and LOT projection in vivo.
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MATERIALS AND METHODS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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). XtJ/XtJ mutant embryos,
which have deletions in the Gli3 gene, were generated as described
previously (Tomioka et al.,
2000). When the XtJ mutation was introduced
into green mice, green mice were crossed with XtJ/+ mice
and the resulting XtJ/+ mice expressing GFP were
intercrossed to obtain XtJ/XtJ green mouse
embryos. Heterozygous netrin 1 mutant mice
(Serafini et al., 1996) and
Dcc mutant mice (Fazeli et al.,
1997) were crossed to obtain homozygous embryos. The day on which
a vaginal plug was found was designated embryonic day 0.5 (E0.5). All
experimental protocols were approved by the Animal Committee of National
Institute of Genetics.
Organotypic culture of telencephalon strips
Each telencephalic hemisphere of the E10.5 mouse embryo was dissected along
the dorsoventral axis into a strip 
1.5 mm wide, including the neocortex,
the presumptive LOT area and the lateral and medial ganglionic eminences (GE)
(see Fig. 1A). In the strip,
the presumptive LOT area was located around the middle along the dorsoventral
axis. In a standard culture, the strip was labeled by injection of dextran
tetramethylrhodamine (D-3308, Molecular Probes, Eugene, OR) or
1,1-dioctadecyl-3,3,3'3'-tetrametylindocarbacyanine perchlorate
(DiI; Molecular Probes) into a small area of the dorsal neocortex, unfolded on
a collagen-coated membrane filter (Transwell-COL inserts #3492, Corning,
Acton, MA) and cultured in Dulbecco's modified Eagle's medium (DMEM)/F-12
(Sigma-Aldrich, St Louis, MO) containing 10% fetal bovine serum (Cansera,
Rexdale, ONT, Canada) and 5% horse serum (Invitrogen, Carlsbad, CA) for 2
days. In co-cultures, explants for combination were prepared from littermates
and cultured as described above. In candidate screenings, HEK293T cells were
transfected with expression plasmids for candidate molecules using FuGENE 6
transfection regent (Roche, Mannheim, Germany) and prepared as cell aggregates
by hanging drop culture (Kennedy et al.,
1994). Each design of culture was repeated at least five
times.
Histochemistry
Immunofluorescent labeling was performed as described
(Tomioka et al., 2000;
Hirata et al., 2002;
Tozaki et al., 2002).
Whole-mount immunostaining of telencephalons with mAb lot1 and anti-neuropilin
1 antibody was described previously (Sato
et al., 1998; Tomioka et al.,
2000). ß-Galactosidase staining followed a method described
previously (Saga et al.,
1992). In situ hybridization was performed as described previously
(Schaeren-Wiemers and Gerfin-Moser,
1993) with mouse Dcc cRNA probe
(Cooper et al., 1995) and mouse
netrin 1 cRNA probe (bp 1-477). In DiI labeling of olfactory bulb axons, a
small crystal of DiI was inserted into the medial part of the olfactory bulb
as described previously (Hirata and
Fujisawa, 1999). For TUNEL assay, In Situ Cell Death Detection Kit
AP (Roche) was used according to the manufacturer's instructions.
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RESULTS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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), this
culture system involves complex procedures and is inadequate for experimental
manipulations. Thus, to analyze the mechanism of the migration in detail, we
developed an organotypic culture system that is easy to manipulate and
applicable for experimental assays. Briefly, a strip including the neocortex
and the GE was prepared from the E10.5 mouse telencephalon along the
dorsoventral axis (Fig. 1A).
The dorsal neocortex of the strip was labeled by injection of a fluorescent
dye, rhodamine, and unfolded on a membrane filter
(Fig. 1B). For the following 2
days in culture, many rhodamine-labeled cells had individually migrated from
the dye-injection point into the ventral tangential direction
(Fig. 1C-E). In general,
migrating neurons are bipolar in shape with a thin trailing process and a
thick leading process orienting towards the direction of their migration.
Indeed, in the organotypic culture, the rhodamine-labeled cells exhibited the
typical morphology, having a thick leading process toward the ventral
direction (Fig. 1C,F). Although
expression of the antigen for mAb Lot1 starts relatively late in the
differentiation of lot cells (Tomioka et
al., 2000), some of the rhodamine-labeled cells migrating in the
neocortex began expressing the antigen for mAb lot1 in organotypic culture
(Fig. 1C).
The ventral migration stream of the labeled cells abruptly terminated
halfway through the strip, exhibiting a sharp boundary
(Fig. 1D,E). This position
coincided with the distal ending of the radial glial palisade dividing the
neocortex and the GE, which was recognizable in immunostaining for reticulon
1, a marker for the neocortex-GE boundary
(Hirata et al., 2002),
indicating that the migration terminal is actually the LOT area
(Fig. 1D). In this area,
labeled cells perpendicularly changed their orientation from the dorsoventral
to rostrocaudal axis and did not penetrate into the ventrally adjacent GE
(Fig. 1G). The migration
pattern of labeled cells in organotypic culture was in accordance with that of
lot cells in whole-embryonic culture and in vivo, thus demonstrating that the
behavior of lot cells was reproducible in the organotypic culture system.
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). In organotypic culture, some rhodamine-labeled
cells in the deeper part of the LOT area were actually found to be
lot1-negative (data not shown), while lot1-positive cells were always detected
on the surface layer. However, the late expression of lot1-antigen made it
impossible to strictly define lot1-positive and -negative cells in the
culture. Therefore, in the following labeling study, we handled all ventrally
migrating cells together as a whole, which contained lot cells.
Unidirectional ventral migration characterizes the telencephalon in the early developmental stage
The dorsal neocortex was isolated from the E10.5 green mouse embryo, in
which all cells expressed green fluorescent protein (GFP), and substituted for
the same dorsal part in the wild-type strip, maintaining the orientation.
Consequently, we obtained a more dramatic image of extensive cell migration; a
great number of green cells migrated from the green dorsal neocortex into the
entire area of the wild-type ventral neocortex, crossing the combination
boundary, although these green cells still respected the neocortex-GE boundary
by terminating the migration (Fig.
2A). By contrast, when the dorsal neocortex isolated from the
wild-type embryo was combined with the ventral neocortex of the green mouse
strip, the green cells did not penetrate into the dorsal neocortex
(Fig. 2B). Therefore, the cells
migrate only ventrally but not dorsally in the 2-day culture of the E10.5
telencephalon.
Previous studies have reported dorsal tangential migration of GABAergic
interneurons from the GE to the neocortex
(Marin and Rubenstein, 2003).
However, dorsal tangential migration was never detected in the above
organotypic culture. This appears to reflect differences in the stages of the
two tangential migration streams; the ventral tangential migration stream is
only transiently seen at the early stage
(Tomioka et al., 2000),
whereas the dorsal migration stream starts at a little later stage
(Tamamaki et al., 1997;
Anderson et al., 2001).
The neocortex contains sufficient directional signals for ventral cell migration
One possible model for ventral tangential migration is its regulation by a
long-range signal secreted by the adjacent region. For example, cells may be
repelled by the dorsomedial margin of the telencephalon called the cortical
hem, or attracted by ventral regions such as the presumptive LOT area and the
GE. To ascertain whether these adjacent regions of the neocortex were
responsible for the ventral tangential migration, the cortical hem, the
presumptive LOT area and the GE were all removed from strips and their
respective contributions to migration were evaluated in culture. Even in the
absence of these adjacent regions, rhodamine-labeled cells still migrated in
the ventral direction within the isolated neocortex down to the ventral edge
(Fig. 2C). The ventral
migration was similarly marked in any region of the neocortex when isolated
and cultured (data not shown). These results suggest that the entire region of
the E10.5 neocortex contains sufficient signals to direct ventral cell
migration (Fig. 2I).
We also co-cultured two dorsal neocortices combined in the dorsoventral mirror image, ventrally facing each other, after labeling only one of the cortices. The labeled cells migrated in the ventral direction down to the combination boundary of the two cortices, but never crossed the boundary nor penetrated into the other cortex combined in the reversed orientation (Fig. 2D). These results suggest that the directional force for the ventral migration is relatively stable and probably created by cues that are displayed over the neocortex in a spatially immobilized manner.
Ventrally migrating cells are excluded from the GE
The ventral migration stream abruptly stopped at the boundary between the
neocortex and the GE, and hardly penetrated into the GE in organotypic culture
and in vivo (Fig. 1D,E),
suggesting some mechanism that prevent ventrally migrating cells from invading
the GE. To test this hypothesis, we combined the dorsal neocortex isolated
from the green mouse embryo with the lateral side of the wild-type strip. In
this type of culture, many green cells migrated into the presumptive LOT area
and the neocortex, but very few invaded the GE
(Fig. 2E). When the green
dorsal neocortex was combined with the ventral side of the GE in the wild-type
strip in the dorsoventrally reversed orientation, the green cells did not
invade the adjoining GE at all (Fig.
2F). Thus, the whole area of the GE was inaccessible to ventrally
migrating cells from any direction, suggesting some mechanisms to prevent the
migration (Fig. 2I).
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Transcription factor Gli3 is cell-autonomously required for the ventral tangential migration
We have previously reported that ventral tangential migration is severely
disrupted in homozygous embryos for the XtJ mutant locus,
which carry a deletion in the gene encoding Gli3, a zinc-finger type
transcription factor (Schimmang et al.,
1992; Hui and Joyner,
1993). In XtJ/XtJ mouse embryos,
lot cells are produced in the neocortex as wild-type embryos, but migrate in
various directions only for a short distance, creating ectopic clusters, and
fail to reach the presumptive LOT area
(Tomioka et al., 2000). We
prepared telencephalon strips from E10.5
XtJ/XtJ embryos and cultured them after
rhodamine-labeling of the dorsal neocortex. The labeled cells hardly migrated
towards the presumptive LOT area, making ectopic clusters over the neocortex
(Fig. 3A,B), which reproduces
the behavior of lot cells in XtJ/XtJ mouse
embryos.
To examine cell-autonomy of the migration defect in the XtJ/XtJ telencephalon, we next co-cultured strips of wild-type and XtJ/XtJ mutant embryos. When the dorsal neocortex from the green mouse was combined with the ventral neocortex of the XtJ/XtJ strip, many green cells that had the wild-type Gli3 gene penetrated ventrally into the combined XtJ/XtJ ventral neocortex and stopped around the presumptive LOT area in the XtJ/XtJ strip (Fig. 3C). By contrast, when the dorsal neocortex isolated from the XtJ/XtJ green mouse was combined with the ventral neocortex in the wild-type strip, XtJ/XtJ green cells barely penetrated into the wild-type neocortex (Fig. 3D). These results indicate that cell-autonomous defects in XtJ/XtJ cells underlie the disturbance of ventral tangential migration in the XtJ/XtJ mouse embryo.
Gli3 functions as a mediator of Shh signaling in the dorsoventral
patterning of the central nervous system
(Jacob and Briscoe, 2003).
Therefore, it is possible that Shh signaling is involved in the ventral
migration. However, the treatment of strips with cyclopamine, an inhibitor of
Shh signaling, did not affect the ventral tangential migration (data not
shown).
Netrin 1 attracts tangentially migrating cells in organotypic culture
We next focused on the molecular mechanism that controls the ventral
tangential migration. Various types of tangentially migrating neurons respond
to axon guidance molecules
(Tessier-Lavigne and Goodman,
1996). Therefore, we selected 11 molecules (netrin 1, netrin
4/ß-netrin, Shh, Sema3a, Wnt1, Wnt3a, Wnt6, Wnt7a, Wnt7b, Slit1 and
Slit2) as candidates and investigated their effects on the ventral tangential
migration by culturing telencephalon strips with cell aggregates expressing
these molecules. Among these candidates, netrin 1, a long-range diffusible
molecule that guides various axons and cells migration
(Kennedy et al., 1994;
Serafini et al., 1994;
Serafini et al., 1996;
Alcantara et al., 2000;
Hamasaki et al., 2001) exerted
obvious attraction for the rhodamine-labeled cells. Many rhodamine-labeled
cells migrated towards the cells secreting netrin 1, ignoring the LOT area
(Fig. 4A,B), but not toward the
mock-transfected control cells (Fig.
4C,D,H).
|
).
From E10.5 to E12.5, while the ventral tangential migration is most marked
(Tomioka et al., 2000), netrin
1 mRNA was strongly expressed in the neuroepithelium of the GE, whereas
Dcc mRNA was expressed on the surface layer of the neocortex, which
contained migrating lot cells (Fig.
5A-C,E-G) in agreement with previous reports
(Cooper et al., 1995;
Schwarting et al., 2004). The
expression of Dcc protein in lot cells was confirmed by double immunostaining
with anti-Dcc and lot1 antibodies (Fig.
5I-M). In the XtJ/XtJ
telencephalon, the expression patterns of netrin 1 and Dcc seemed
essentially conserved in spite of severe dysplasia
(Fig. 5D,H). We used the netrin 1-lacZ knock-in mutants to mark the expression of the netrin 1 gene in whole-telencephalon preparations. In the heterozygous knock-in telencephalon, the neuroepithelium of the GE was lacZ-positive from E10.5 onwards (Fig. 6C), which well reflected the endogenous expression patterns of netrin 1 shown by in situ hybridization (Fig. 5A-C). In addition, after E13.0, the strong expression of lacZ manifested in the rostroventrally restricted area in the telencephalon beneath the olfactory bulb, corresponding to the rostral part of the olfactory tubercle (Fig. 6F,G). In situ hybridization also detected the expression of netrin 1 mRNA in cells that occupied the surface area of this part at E12.5 (Fig. 5C). Thus, in later embryonic stages, netrin 1 is expressed on the surface area of the olfactory tubercle, in addition to the neuroepithelium of the GE.
|
|
). By
E12.5, differences in the distribution of lot cells between wild-type and
homozygous mutant embryos were not evident; lot cells were dorsally restricted
in the presumptive LOT area, shaping a narrow cellular array, in both of the
genotypes (Fig. 6A,B). From
E13.0 onwards, the distribution of lot cells ventrally expanded in wild-type
and heterozygous embryos; lot cells covered the ventral part of the LOT area
and particularly widely spread the rostral part that continued from the
olfactory bulb (Fig. 6D,G).
Therefore, the ventrolateral side of the olfactory bulb was now surrounded by
lot cells, broadening the rostral part of the cellular array. The front of
this ventral expansion of lot cells abutted the netrin 1-expressing domain in
the rostral olfactory tubercle (Fig.
6G,I). In the homozygous mutant embryos, the distribution of lot
cells did not expand ventrally even after E13.0, leaving the ventral part of
the LOT area unoccupied by lot cells (Fig.
6E,H,J). The dense pack of lot cells in the ventral margin of the
cellular array delineated the edge more sharply
(Fig. 6E,H,L) compared with
wild-type and heterozygous embryos (Fig.
6D,G,K). Dcc mutant embryos
(Fazeli et al., 1997)
phenocopied the above abnormal distribution of lot cells (data not shown).
These results suggest that netrin 1-Dcc signaling controls the late phase of
ventral migration of lot cells in vivo, specifically when the cells migrate
further ventrally from the LOT, where the late expression of netrin 1 in the
rostral tubercle seems functional.
Because the organotypic culture of telencephalon strips only reproduces the
early phase of ventral tangential migration, the migration defects of
Dcc or netrin 1 mutant embryos were undetectable, and the cells
migrated seemingly normally when the mutant strips were cultured
(Fig. 4E), even though the
cells in homozygous Dcc mutant strips completely lost the reactivity
to exogenous source of netrin 1 (Fig.
4F,H). Therefore, the initial stage of the ventral migration can
progress without netrin 1-Dcc signaling, which presents a contrast to the
early migration defect in XtJ/XtJ mutant
embryos. During ventral attraction of commissural axons in the spinal cord,
netrin 1 and Shh have redundant functions, and Shh partially compensates for
the axonal defect resulting from the loss of netrin 1-Dcc signaling
(Charron et al., 2003). We
therefore suspected compensatory action of Shh in the mutants and blocked the
Shh signaling by cyclopamine in homozygous Dcc mutant strips.
However, the ventral migration was still normally observed in the strips
(Fig. 4G), suggesting that
neither Shh nor netrin 1-Dcc signaling is required for the early phase of
ventral tangential migration.
|
), the
aberrant distribution of lot cells in netrin 1 and Dcc mutant embryos
may cause a defect in the projection of these axons. Thus, we investigated the
trajectory of olfactory bulb axons in whole-mount immunostaining for
neuropilin 1, a marker of these axons. The axons, originating from the medial
part of the olfactory bulb, encircled the bulb via either the ventral or
dorsal side before converging onto to the LOT. Similar numbers of axons were
normally found to take the ventral and dorsal pathways
(Fig. 7A,C). In netrin 1 and
Dcc homozygous mutant embryos, the axons projecting through the
ventral pathway were markedly reduced compared with those in the wild-type and
heterozygous embryos. The mutations, however, did not seem to influence the
axons in the dorsal pathway nor the overall trajectory of LOT axons after
convergence of the two pathways (Fig.
7A,B). This axonal defect in the ventral pathway was detected from
E13.5 and was clearly visible after E14.5 by immunostaining. Fluorescent dye labeling of axons from the medial olfactory bulb specified the defect in the ventral pathway in more detail. In wild-type and heterozygous embryos, the axons taking the ventral pathway smoothly projected over the rostroventral part of the LOT area, which had received the late invasion of lot cells, and adjoined the ventral margin of the LOT bundle, keeping the orderly arrangement among the neighboring axons (Fig. 7E,G). In the homozygous embryos, the axons through the ventral pathway were tangled and often formed an off-course bundle that strayed from the LOT. These aberrant bundles usually turned back into the bulb, forming a focused terminus on the dorsolateral position of the olfactory bulb (Fig. 7F,H).
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DISCUSSION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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;
Hasegawa et al., 2004).
|
;
Arakawa, 2004). However, we
confirmed that apoptosis is only enhanced in the netrin 1 mutant, but not the
Dcc mutant telencephalons (see Fig. S1 in the supplementary
material), as expected by the dependence receptor hypothesis
(Bredesen et al., 2005).
Therefore, the phenotypes observed in the mutant telencephalons can not be
attributed to the excessive death of lot cells or their surrounding tissues,
but appear to be direct consequences of the impaired reception of netrin 1-Dcc
signaling in cells of the ventral migration stream. In conclusion, netrin 1 is
suggested to function as a local attractant in the ventral area that controls
the late phase of ventral migration.
What, then, controls the early phase of ventral migration? In
XtJ mutant telencephalons, the early phase of the
migration was severely disrupted, even though netrin 1 and Dcc were
expressed in the appropriate time and place. The responsible gene for the
XtJ mutation, Gli3, was cell-autonomously
required in the ventrally migrating cells, probably for their actual movement
or reception of guidance signals. Gli3 is a downstream component of Shh
signaling (Jacob and Briscoe,
2003), and Shh acts directly as a chemoattractant on axons in the
spinal cord, collaborating with netrin 1
(Charron et al., 2003).
However, the present study did not support the direct involvement of Shh in
guidance of the ventral migration stream, because inhibition of Shh signaling
by cyclopamine did not affect the ventral migration, even under conditions
lacking netrin 1-Dcc signaling. The candidate screening of guidance molecules
also failed to detect apparent activity of Shh for the ventral migration
stream, although this ectopic supply of Shh severely affected morphogenesis
and patterning of telencephalon strips in culture and hampered the high
sensitive analysis (data not shown). Because Gli3 is more than just a Shh
mediator (Liu et al., 1998;
Mullor et al., 2001), this
transcription factor may mediate other signals in the cells during the ventral
migration.
The combination culture demonstrated that the GE rigidly excludes the
ventral migration stream. However, the GE is not a complete obstacle to all
cell migrations, because other neuron types migrate through the GE. For
example, a fraction of reelin-positive cells tangentially migrate onto the
surface of the GE at the embryonic stage similar to that for lot cells
(Takiguchi-Hayashi et al.,
2004), and progenitors of cortical interneurons vigorously migrate
through the deeper region of the GE at a later stage
(Marin and Rubenstein, 2003).
Thus, not the simple physical structure of the GE but target cell-specific
mechanisms appear to operate for the exclusion of ventrally migrating cells.
Because the GE did not repel the migrating cells from a distance, short-range
guidance molecules appear to be responsible for this exclusion.
Lot cells construct the cellular array between the neocortex and the GE,
where the two types of guidance signals, the ventrally directed driving force
in the neocortex and the short-range repulsion by the GE, are confronting each
other. This encounter between these two signals may be sufficient for lot
cells to alter their cellular arrangement, because the cells changed their
orientation and aligned along the artificial boundary on which the neocortex
and the GE were directly combined. In fact, the presumptive LOT area between
the two compartments may not be essential for formation of the cellular array.
A previous study reported that in Pax6 mutant embryos, although many
characteristics of the neocortex-GE boundary are missing
(Stoykova et al., 1997), lot
cells were still capable of forming a continuous cellular array on the area
adjacent to the GE (Hirata et al.,
2002).
|
;
Inaki et al., 2004), it is
possible that olfactory bulb axons are directly guided by netrin 1, so that
the axons in the mutant embryos are misdirected as a direct consequence of the
loss of netrin 1-Dcc signaling. However, netrin 1 does not exert any apparent
effects on olfactory bulb axons in culture
(Li et al., 1999;
de Castro et al., 1999), and
therefore we could not address this possibility any further. Secondly, the
pathfinding error in the mutants might to be indirectly induced by the
aberrant distribution of lot cells. The route for the ventral pathway of
olfactory bulb axons involves the rostroventral part of the LOT area, which is
normally populated with abundant lot cells. In the absence of netrin 1-Dcc
signaling, the distribution of lot cells into this area was abandoned and, at
the same time, the axons coursing through this area showed the most severe
defects (Fig. 8). Thus,
considering that lot cells are required for the guidance of olfactory bulb
axons (Sato et al., 1998), the
loss of lot cells around the area could have serious consequences for the
axons in the ventral pathway.
The results of the present and previous studies
(Tomioka et al., 2000) suggest
that, in addition to lot cells, other cell populations tangentially migrate in
the ventral direction in the developing neocortex. Reelin-positive marginal
zone cells are generated from the caudomedial wall of the telencephalon and
distributed almost over the entire neocortex and part of the GE by tangential
migration (Takiguchi-Hayashi et al.,
2004). As lot cells do not express reelin
(Sato et al., 1988), these two
types of cells appear to belong to different cell populations but migrate in
the routes overlapping to some extent. Another recent study has revealed a
ventral tangential migration stream of olfactory cortical neurons that is
seemingly very similar to that of lot cells but governed by a distinct stop
signal (T. Nomura and N. Osumi, personal communication). These observations
taken together support the view that multiple neuronal populations migrate
simultaneously in the ventral direction on the early embryonic neocortex.
Although this migration mode had been somehow overlooked until recently, the
present study clearly shows that the ventral tangential migration is the most
common migration mode in the early telencephalon when neurogenesis has just
started, and therefore has immeasurable impact on all the following processes.
Hence, it is of great interest to determine the precise constituents,
migration mechanisms and physiological functions of these processes in the
future.
|
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/133/5/845/DC1
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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