1 Graduate School of Frontier Biosciences, Osaka University, Machikaneyama 1-3,
Toyonaka, Osaka 560-8531, Japan
2 Laboratory of Neurochemistry, National Institute for Physiological Sciences,
Myodaiji, Okazaki, 444-8585, Japan
3 The Graduate University for Advanced Studies, Hayama, Kanagawa 240-0193,
Japan
4 SORST, Japan Science and Technology Corporation, Kawaguchi, 332-0012,
Japan
5 Division of Behavior and Neurobiology, Department of Regulation Biology,
National Institute for Basic Biology, Myodaiji-cho, Okazaki 444-8585,
Japan
Author for correspondence (e-mail:
murakami{at}fbs.osaka-u.ac.jp)
Accepted 18 August 2003
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SUMMARY |
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Key words: Neuronal migration, GABAergic interneuron, Neocortex, Time-lapse analysis, PI-PLC, Gad67, GPI-anchored protein, Tag1
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Introduction |
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A number of studies have attempted to provide a phenomenological
description and to elucidate the mechanisms of the migration of GABAergic
neurons from the GEs to the cortex. These include labeling of GE neurons with
fluorescent dyes followed by in vitro culture
(de Carlos et al., 1996;
Tamamaki et al., 1997
;
Lavdas et al., 1999
;
Anderson et al., 2001
;
Jimenez et al., 2002
;
Nadarajah et al., 2002
),
analysis of transgenic animals lacking genes that affect GEs
(Anderson et al., 1997
;
Casarosa et al., 1999
;
Sussel et al., 1999
) and
transplantation of tagged tissues (Anderson
et al., 2001
; Wichterle et
al., 2001
; Nery et al.,
2002
; Polleux et al.,
2002
). In vitro experiments suggested the possible involvement of
repellent molecules such as slits (Zhu et
al., 1999
; Wichterle et al.,
2003
) and semaphorins
(Marín et al., 2001
;
Tamamaki et al., 2003
).
Recently, an axonal surface molecule, Tag1 (previously TAG-1) expressed by
corticofugal axons, has been suggested to serve as a substrate for the
migration of GE-derived cortical neurons
(Denaxa et al., 2001
).
Moreover, it has also been shown that hepatocyte growth factor (HGF) can act
as a motogen for these neurons (Powell et
al., 2001
). It appears that cues in the cortex also contribute to
the migration of these neurons
(Marín et al.,
2003
).
After entering the neocortex, GE-derived GABAergic neurons are thought to
distribute over the entire cortex, while the remainder continue migration to
the hippocampus (Pleasure et al.,
2000). However, little is known about the migration of these
neurons within the cortex. To understand how the GE-derived neurons are sorted
in the cortex to distribute as cortical interneurons, we visualized
intracortical migration of GE-derived neurons, using glutamate decarboxylase
(GAD) 67-green fluorescent protein (GFP) knock-in mice, in which GFP is
specifically expressed in GABAergic neurons. This transgenic animal has
allowed us to analyze systematically the distribution of cortical GABAergic
neurons in fixed sections and the dynamics of the migration of these neurons
in acute slices as well as flat-mount preparations of the cortex,
respectively. We report that cortical GABAergic neurons exhibit several modes
of migration: ordered migration in a ventrolateral-to-dorsomedial direction
along the lower IZ and the subventricular zone (SVZ); radial and non-radial
migration towards the pial surface; multidirectional migration in the
tangential plane of the marginal zone (MZ); and radial migration from the MZ
to the cortical plate (CP). Intracortical migration of GABAergic neurons was
not affected after treatment by an enzyme that cleaves
glycosylphosphatidylinositol (GPI) anchors, suggesting that substrates other
than GPI-anchored proteins regulate intracortical migration of these neurons.
We propose a model that would explain the significance of multimodal migration
of cortical GABAergic neurons.
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Materials and methods |
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All studies were carried out in accordance with the guidelines of the Animal Studies Committee of Osaka University.
Observation of fixed brains
To visualize GFP+ cells in fixed tissues, embryos at E12.5, 13,
13.5 or 15.5 either heterozygous or homozygous for the Gad67-GFP allele were
killed, decapitated and the brains were dissected out. The brains were fixed
in 4% paraformaldehyde from 6 hours to overnight at 4°C and transferred to
phosphate buffer (0.1 M, pH7.4) or phosphate-buffered saline. They were then
mounted onto a stage of a vibrating microtome (VT-1000, Leica Microsystems,
Tokyo, Japan) and sectioned coronally at 50 µm. The sections were
transferred to slides and coverslipped. Images were then captured from either
side of the cortex using a CCD camera (Axiocam, Zeiss, Jena, Germany) attached
to an epifluorescence microscope (BX-60, Olympus, Tokyo, Japan) and stored in
a hard disk. Mirror images of captured files were created using Adobe
PhotoShop software (ver. 6.0) as necessary.
To determine the zone of neuronal migration, Nissl staining with Methylene Blue was performed on adjacent sections.
In order to immunostain for GABA, anti-GABA rabbit polyclonal antibody (1/2000 dilution, Sigma, St Louis, MO) was applied, for 2 hours at room temperature, to 10 µm cryostat sections obtained from heterozygous mice embryos fixed in a fixative containing 0.1% glutaraldehyde, 4% paraformaldehyde and 0.2% picric acid in phosphate buffer (0.1 M, pH 7.4). Thereafter, Cy3-conjugated anti rabbit IgG (1/300 dilution, Jackson ImmunoRes, West Grove, PA) was applied for 1 hour at room temperature. For Tag1 staining, supernatant of 4D7 monoclonal antibody (a gift from Dr Miyuki Yamamoto) was applied to 20 µm cryostat sections followed by Cy3-conjugated anti mouse IgM (1/500 dilution, Jackson ImmunoRes). To immunostain for microtubule-associated protein 2 (MAP2), an anti-MAP2 mouse monoclonal antibody (HM-2, Sigma) was applied at 1:500 dilution for 3 hours at RT to 12 µm cryostat sections obtained. This was followed by incubation in Cy3-conjugated anti rabbit IgG (1/500 dilution, Jackson ImmunoRes) for 1 hour at room temperature. Heterozygous mice embryos fixed in 4% paraformaldehyde were used for Tag1 and MAP2 staining.
Time-lapse imaging in coronal slices
Brains of E13.5 or E15.5 mouse embryos either heterozygous or homozygous
for the Gad67-GFP allele were embedded in 4% low melting-point agarose.
Coronal slices were then cut at 250 µm, using a vibrating microtome. Slices
were selected from the anterior half of the cerebral hemispheres, at the level
that includes the lateral and medial ganglionic eminences (LGE and MGE,
respectively), and mounted on membrane inserts (Millicell-CM Low Height
Culture Plate Inserts, Millipore, Bedford, MA). The membrane was coated with
poly-L-lysine (1 µg/ml) prior to tissue mounting. Brain slices were covered
with a thin layer of collagen gel and soaked in 5% or 10% fetal bovine serum
in Hanks' solution (Nissui, Tokyo) supplemented with D-glucose (6
mg/ml) and streptomycin (Sigma, 20 mg/l). In some cases, insulin (10 µg/ml)
and transferrin (100 µg/ml) were added to the solution. A coverslip was
placed over the Millicell insert to prevent evaporation, and the preparation
was transferred to a temperature-controlled (36-38°C) plastic chamber
fitted onto a confocal microscope stage (MRC-1024, Biorad, Hercules, CA).
GFP+ cells were viewed through an objective (x20, N.A.=0.4
each) of an upright light microscope (BX-50, Olympus, Tokyo). Images were
collected using 488 nm excitation and 522/35 nm emission filters from the
dorsolateral cortex, at a depth of 40-80 µm below the cut surface of the
slice. To follow the movement of cells continuously, images were taken every 5
minutes for up to 3 hours. Cell motility did not decrease systematically with
time, suggesting that the cells were healthy. The health of migrating cells
was further checked by carefully comparing migratory behavior of neurons with
morphological features observed in fixed slices of corresponding developmental
stages. In some slices, we observed aberrant migratory behavior not seen in
fixed slices such as abundant migrating cells in the VZ. Such behavior was
likely to be an artifact and was therefore interpreted with caution.
Phosphatidylinositol-specific phospholipase C (PI-PLC) treatment
Cortical slices prepared as above and embedded in collagen gels were kept
for 20 minutes. Time-lapse imaging was started after incubation of the slices
in 0.5 U/ml PI-PLC (Molecular Probes, Eugene, OR) for 2 hours at 37°C.
Some of the slices were fixed immediately after the incubation to examine the
effect of PI-PLC. After time-lapse imaging, which normally took 1.5 hours, the
slices were fixed and immunostained for Tag1
(Yamamoto et al., 1986;
Dodd et al., 1988
).
Time-lapse imaging in flat-mount cortical preparation
The methods for observation were essentially the same as those for slice
preparations. E13 or E13.5 mouse embryo neocortical tissue was dissected
encompassing from the medial edge to the corticostriatal boundary, at the
level of the MGE and the LGE. The cortical tissue was then flat mounted on
Millicell inserts with the ventricular side down. The recording was carried
out for 90-165 minutes at 5 minutes intervals. At every time point, stack of
images were created from a series of 3-6 consecutive images taken along the
z-axis at 5 or 10 µm intervals.
Quantitative analysis of migratory behaviors
For quantification of migratory behaviors, slice preparations in which the
distribution of GFP+ cells closely resembled that in fixed
preparations at the end of the time-lapse analysis were selected. Owing to the
high density of GFP+ cells, it was not possible to trace all
labeled cells. Thus, the analysis was carried out for all individually
distinguishable GFP+ cells. From the position of each cell, a
vertical line was drawn to the ventricular surface. Another line was then
drawn connecting the initial position of the neuron and the position after 95
or 105 minutes observation. The direction of migration was defined by the
angle of the line relative to the vertical line. The distance of migration was
defined as the length of this line, and this was divided by observation time
to calculate average speed of migration. Because migration of neurons away
from the midline was also observed, deflection from the line oriented
ventrolaterally was represented by negative angles.
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Results |
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At E15.5, the cerebral wall was thicker and numerous GFP+ cells appeared in it (Fig. 1C). The increase in cell density was remarkable in the MZ and the SVZ. The majority of IZ GFP+ cells had mediodorsally oriented leading processes, roughly parallel to the pial surface (Fig. 1C, arrow 1, left inset). As was the case at E13.5, high cell density seems to be hampered recognition of leading processes of the MZ GFP+ cells. In the SVZ, cell density was also high, but tangentially oriented leading processes were frequently observed (data not shown). We also observed that a substantial number of cells extended processes in non-tangential directions. This included pial surface and ventricle-oriented cells, but the former appeared to be predominant (Fig. 1C, arrows 2 and 3, middle and right insets). Ventrolaterally oriented cells (towards the basal forebrain) were also observed, albeit few in number (data not shown).
As development proceeds further, the cerebral wall became thicker and a larger number of radially oriented GABAergic neurons were observed in the cortical plate (data not shown).
The distribution of GFP+ cells in the cortex was consistent with
that of GABA immunoreactive neurons (Del
Rio et al., 1992; Jimenez et
al., 2002
), indicating that GFP+ cells observed here
are likely to be GABAergic neurons. Immunolabeling of GFP+ cells
with anti-GABA and anti-MAP2 antibodies confirmed that most of them indeed
correspond to GABA immunopositive neurons (data not shown).
Dynamics of migration in acute coronal slices of the cortex
To examine intracortical migration of GABAergic neurons directly, we
observed GFP+ cells in coronal slices in time-lapse sequences. As
expected, GFP+ cells were highly motile in E13.5 lower IZ
(Fig. 2A,E; see Movie 1 at
http://dev.biologists.org/supplemental/).
However, most MZ GFP+ neurons showed limited motility
(Fig. 2F, yellow dots),
although some showed tangential migration (see Movie 1 at
http://dev.biologists.org/supplemental/).
In deeper zones of the cortex, many neurons were motile, migrating medially
and occasionally deflected toward the MZ. Similar behavior of GFP+
neurons was observed in 12 slices. These observations suggest that
intracortical tangential migration takes place mainly in the lower IZ at this
stage and raise the possibility that some neurons in the lower IZ translocate
to the MZ.
|
Migration of GABAergic neurons in flat-mount cortical
preparations
GABAergic neurons in the MZ showed limited motility when observed in
coronal slices. However, this does not preclude the possibility that, in vivo,
they migrate in directions not detectable in coronal slices. The flat-mount
preparations of the cortex enabled us to test this possibility.
Figure 3A-C shows confocal
images of the dorsal view of the cortex captured at appropriate time intervals
in an E13 mouse. It is likely that these represent MZ neurons as they are
located near the surface of the cortex. At this stage, the leading edge of
GFP+ neurons was observed in the lateral cortex
(Fig. 3C, inset). At the
leading edge, it was possible to observe the morphology of individual
GFP+ neurons because of their relatively low density. Time-lapse
sequences indicated that some GFP+ neurons showed pronounced
motility in the tangential plane extending and retracting their processes (see
Movie 3 at
http://dev.biologists.org/supplemental/).
Near the leading edge, some cells showed lateral-to-medial migration
(Fig. 3C, arrows). In the
region behind the leading edge, however, many GFP+ neurons appeared
stationary (see yellow cells in Fig.
3C; see Movie 3 at
http://dev.biologists.org/supplemental/)
and medially directed migration of GFP+ neurons was not
recognizable as a whole (n=7). At E13.5, the leading edge progressed
medially (Fig. 3E, inset),
enabling us to observe the motility of the cells behind the leading edge by
observing the lateral cortex. In this region, a fraction of GFP+
neurons showed low motility (Fig.
3D-F). However, many of them quickly migrated among stationary
cells (Fig. 3F). This migration
of individual neurons occurred in many directions (n=17) (see Movie 4
at
http://dev.biologists.org/supplemental/).
It was difficult to observe migration of individual cells in flat-mount
preparations of E15.5 mice because of high cell density, but the cells at this
stage also appeared to exhibit multidirectional migration at this stage (data
not shown). Thus, the observation in the flat-mount preparation has revealed
that a substantial proportion of MZ neurons migrate in all directions. The
virtual absence of lateral-to-medial migration of GFP+ cells as a
whole is consistent with the observation of coronal slices and indicates that
MZ neurons do not show obvious lateral-to-medial tangential migration.
|
|
The results of the quantification clearly demonstrated occurrence of multidirectional tangential migration, in the coronal plane, biased towards the pial surface. They also showed that lateral-to-medial migration of these neurons mainly occurs in the IZ/SVZ.
Effect of GABA content on the migration of GABAergic neurons
It is possible that individual cell GABA content is reduced in Gad67-GFP
knock-in mice. This might cause a decrease in GABA concentration in the
cortex. Neuronal migration in Gad67-GFP mice might be distorted, because there
is in vitro evidence that GABA affects neuronal migration
(Behar et al., 2001). To test
this possibility, we observed the morphology and migratory behavior of
GFP+ neurons using mice homozygous for the Gad67-GFP allele
(Gad67gfp/gfp), comparing it with that of heterozygous mice
(Gad67gfp/+). Remarkable reduction in GABA content in
Gad67/ mice that had been generated using a
similar construct (Asada et al.,
1997
) suggests that GABA content may also be greatly reduced in
Gad67gfp/gfp animals. In fixed slices, no differences were noted
between heterozygous and homozygous mice in the distribution, zone-specific
features or cellular morphology of GFP+ neurons either in E13.5
(n=5: Fig. 5A) or
E15.5 (n=5: Fig. 5B)
embryos. Similarly, all features of migratory behaviors as described above
were observed in homozygous mice (Fig.
5C,D). We also did not find notable differences in the rate and
orientation of migrating GFP+ neurons (compare
Fig. 5C,D with
Fig. 4A,C). These results
suggest that a reduction of GABA content does not significantly affect the
migratory behavior of GABAergic neurons, at least within the time window of
our observation. This notion is further supported by the observation that
gross structure of the brain appears normal in newborn
Gad67/ mice
(Asada et al., 1997
).
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Discussion |
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Using Gad67-GFP mice allowed us to overcome some technical limitations
associated with previous studies. First, we could observe the migration of
virtually all GABAergic neurons, while the use of Dil
(1,1-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate)
labeling (Tamamaki et al.,
1997; Jimenez et al.,
2002
) and tissue transplantation allows the observation of only a
subpopulation of migrating cells of unknown identity, possibly including glial
cells or their progenitors (Spassky et
al., 1998
; Olivier et al.,
2001
). This has made it possible to precisely assess the role of
candidate molecules that regulate migration. Second, omission of staining
procedures together with strong fluorescence emissions enabled us to observe
migrating cells in flat-mount preparations in an in vivo-like environment,
which has provided important information of neuronal migration.
It is noteworthy that there were neurons that extended leading processes but did not migrate within the window of our time lapse analysis. This indicates that observation of fixed tissues does not necessarily provide accurate information on the dynamic behavior of these neurons.
Zone-specific migration of GABAergic neurons
Robust lateral-to-medial tangential migration observed in the lower IZ/SVZ
of the dorsal cortex implies that a part of GABAergic neurons migrating in
these zones further migrate away from the cortex. This is consistent with the
notion that GE-derived neurons migrate further to the hippocampus
(Pleasure et al., 2000).
GFP+ neurons were also abundant in the MZ. Previous studies
using in vitro slices labeled with fluorescent dyes provided evidence that
GE-derived cells migrate along the MZ (de
Carlos et al., 1996; Lavdas et
al., 1999
; Jimenez et al.,
2002
; Polleux et al.,
2002
) as well as the IZ. Our findings that in fixed preparations
the dorsal leading edge of the migratory stream elongated dorsomedially and
that the density of GFP+ neurons in the MZ increased as development
proceeded (Fig. 1) are
consistent with these observations. Unexpectedly, however, MZ GFP+
neurons as a whole did not show obvious directed tangential migration both in
flat-mount preparations and coronal slices. One possible explanation for this
apparent discrepancy is that medial extension of the MZ that includes
GFP+ neurons resulted from supply of neurons from deeper zones of
the neocortex. Indeed, in fixed tissues, we found many migrating neurons
between the IZ and the MZ oriented towards the pial surface. Consistent with
this, a substantial number of neurons did migrate from the lower IZ/SVZ
towards the MZ in our in vitro coronal slice preparations. An interesting
scenario, therefore, is that a part of the tangentially migrating neurons in
the lower IZ/SVZ deflect towards the MZ
(Fig. 8), contributing neurons
to the layer of GABAergic neurons in the MZ.
|
Multidirectional migration in the MZ
In this study, we have demonstrated multidirectional tangential migration
of identified GABAergic neurons in the MZ for the first time using flat-mount
preparations of the cortex. These neurons appeared to migrate in random in
this plane, suggesting it unlikely that this migration contributes
significantly to lateral-to-medial tangential expansion of GABAergic neurons
in the cortex. Cortical GABAergic neurons originate from specific regions in
the basal forebrain, primarily from the MGE, and migrate tangentially towards
the cortex (see Introduction). However, it has remained unknown how they
become widely distributed in the cortex. Multidirectional migration of
GABAergic neurons in the MZ might explain the spread of GABAergic neurons over
the entire cortex at least in part.
Implication to the mechanism of intracortical migration of GABAergic
neurons
In vitro, GABA acts as a chemoattractant for cortical neurons
(Behar et al., 2001) and
inhibition of GABAB receptors modulates the migration of cortical
interneurons (Lopez-Bendito et al.,
2003
). These findings raise the possibility that GABA may be
involved in the migration of cortical interneurons. However, in this study no
notable difference was found in the distribution, cellular morphology or
migratory behaviors of GABAergic neurons between heterogygous
(Gad67gfp/+) and homozygous (Gad67gfp/gfp) mice, in
which GABA should be greatly diminished. These findings suggest that GABA does
not play an important role in the intracortical migration of GABAergic
neurons, although a low level of GABA could be sufficient to regulate their
migration.
Recently, corticofugal axons have been suggested to provide a substrate for
tangential migration in the IZ (Denaxa et
al., 2001). However, this fails to explain the multidirectional
migration of GABAergic neurons observed in the coronal plane. Moreover,
incomplete overlap of the migratory stream with axonal tracts
(Wichterle et al., 2001
)
suggests that the axonal tract may only partially serve as a substrate. The
present finding that the major stream of GFP+ migrating neurons did
not coincide with Tag1+ fibers is consistent with this idea.
Moreover, we showed that all features of the migration of GABAergic neurons
within the cortex were unaffected by PI-PLC treatment. This indicates that
GPI-anchored proteins including Tag1 are not required for intracortical
migration of GABAergic neurons. Thus, unidentified factors may contribute to
the establishment of the substrate of migration within the cortex. Although
the present results do not preclude the possibility that Tag1 plays an
important role in the migration of GABAergic neurons from the MGE to the
cortex (Denaxa et al., 2001
),
the lack of changes in gross anatomy of the cerebral cortex in Tag1-deficient
mice (Fukamauchi et al., 2001
)
further supports the notion that Tag1 plays a limited role in the development
of the cerebral cortex.
There was a diversity of behavior of GABAergic neurons even in a given zone
of the cortex. The ability to classify GABAergic neurons into several
subtypes, depending on biochemical properties, morphology and
electrophysiological properties (Kawaguchi
and Kubota, 1997), raises the possibility that such diversity of
migratory behavior reflects the inherent diversity of GABAergic neurons.
Alternatively, even if these neurons uniformly respond to guidance cues, there
might be some stochastic process in the machinery that mediates the signaling
of guidance molecules. It is also possible that the intrinsic program of
migrating GABAergic neurons contributes to their behavioral diversity
(Yacubova and Komuro,
2002
).
Recently, ventricle-directed migration of GABAergic neurons was shown to be
prevalent in E16-18 embryonic rat cortical slices
(Nadarajah et al., 2002). Such
neurons may seek the cortical VZ to receive layer information. The proportion
of such neurons was low in our preparations, however. Further studies should
reveal whether this is due to differences in preparations or in the method of
labeling neurons.
In conclusion, Gad67-GFP knock-in mice enabled us to analyze the in situ migration of GABAergic neurons in the neocortex. This has allowed us to compare the migratory behavior of GABAergic neurons in different zones and to assess the role of GPI-anchored proteins. Moreover, it has revealed the presence of several modes of intracortical migration of GABAergic neurons: directed tangential migration in the IZ/SVZ possibly towards the hippocampus, migration towards the MZ, multidirectional tangential migration in the MZ and migration away from the MZ. These modes of migration were not affected by PI-PLC treatment, suggesting that GPI-anchored proteins are not important for these migrations. We propose a model that cortical GABAergic neurons initially invade the MZ by departing from the major migratory stream in the IZ/SVZ and then disperse in the MZ. Some of these neurons may descend away from the MZ to be distributed in the CP.
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ACKNOWLEDGMENTS |
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Footnotes |
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* These author contributed equally to this work
Present address: YN, Nippon Shinyaku. Co., Ltd, 14,Nishinosho-Monguchi-cho,
Kisshoin, Minami-ku, Kyoto 601-8550, Japan; KO, BSI, Riken, Hirosawa 2-1,
Wako, 351-0198, Japan
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