Institute of Anatomy and Cell Biology, Albert-Ludwigs-Universität Freiburg, Albertstr. 17, 79104 Freiburg, Germany
* Author for correspondence (e-mail: michael.frotscher{at}anat.uni-freiburg.de)
Accepted 27 July 2004
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SUMMARY |
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Key words: Neuronal migration, Layer formation, Radial glia, Reelin, reeler mouse, Dentate gyrus
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Introduction |
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An alternative function of reelin was recently suggested by Förster et
al. (Förster et al.,
2002), who showed that Disabled1 (Dab1), a molecule of the reelin
signaling cascade (Howell et al.,
1997
; Sheldon et al.,
1997
; Ware et al.,
1997
), is expressed by glial fibrillary acidic protein
(GFAP)-positive radial glial cells in the dentate gyrus. They also found a
malformation of radial glial processes in the reeler dentate gyrus
and concluded that reelin controls the migration of dentate granule cells by
acting on the radial glial scaffold required for migration
(Förster et al., 2002
;
Frotscher et al., 2003
;
Weiss et al., 2003
).
Reelin, which is secreted by CR cells in the marginal zone, forms a
component of the local extracellular matrix. It has remained open to question
whether this specific distribution of reelin is crucial for its function.
Previous studies that addressed this issue
(Magdaleno et al., 2002)
showed that heterotopic reelin expression partially rescued the migration
defects in the reeler mutant, suggesting that reelin does not
function simply as a positional signal. In line with this study, incubation of
slices from embryonic reeler neocortex in the presence of recombinant
reelin partially rescued the reeler phenotype
(Jossin et al., 2004
).
Here, we have used slice cultures of postnatal reeler hippocampus and recombinant reelin to study the effects of reelin on neuronal migration in the dentate gyrus, a brain region known for its late, largely postnatal neurogenesis. Our findings suggest that reelin acts as both a differentiation factor for radial glial cells, and a positional signal for radial fiber orientation and granule cell migration in the dentate gyrus.
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Materials and methods |
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For the preparation of co-cultures, hippocampal slices of newborn
reeler mice were positioned in close vicinity to the outer molecular
layer of the dentate gyrus of slices from wild-type mice or young Wistar rats
(P2-P5), so that the dentate gyrus of the reeler slice came in direct
contact with the reelin-containing marginal zone of the wild-type slice (see
Fig. 3A). Slices were placed
onto Millipore membranes and transferred to a six-well plate with 1 ml/well
nutrition medium (25% heat-inactivated horse serum, 25% Hank's balanced salt
solution, 50% minimal essential medium, 2 mM glutamine, pH 7.2). Slices were
incubated as static cultures in 5% CO2 at 37°C for 7 to 10 days
(Stoppini et al., 1991). The
medium was changed every 2 days.
|
Transfection of 293 cells with the full-length reelin cDNA and preparation of reelin-containing and control supernatants
293 cells were transfected with the full-length reelin clone pCrl, a
generous gift of Dr T. Curran (D'Arcangelo
et al., 1997), as described elsewhere
(Förster et al., 2002
).
In brief, full-length reelin-synthesizing clones were identified by RT-PCR,
using various primer pairs spanning different parts of the reelin cDNA, and by
immunocytochemistry and western blotting of cell supernatants employing the
G10 antibody against reelin, kindly provided by Dr A. Goffinet
(de Bergeyck et al., 1998
).
Reelin-enriched supernatants and control supernatants were obtained from
serum-free incubation medium of reelin-transfected 293 cells and green
fluorescent protein-transfected control cells, respectively. Reelin content
was confirmed by western blotting using the G10 antibody
(Förster et al., 2002
;
Frotscher et al., 2003
).
Treatment of reeler cultures with recombinant reelin
Supernatant (200 µl) from reelin-synthesizing 293 cells was added to
each well containing 1 ml normal nutrition medium. In addition, 1 µl of
this supernatant was directly applied to each individual reeler
hippocampal culture 3 times a day from day in vitro (DIV) 0 to DIV 7
(n=16). As a control, 200 µl of the supernatant from 293 cells
transfected with a plasmid encoding for green fluorescent protein (GFP) were
added to the medium of each well containing 1 ml normal nutrition medium, and
1 µl of this supernatant was applied to each reeler culture
(n=12).
Incubation of hippocampal co-cultures with the CR-50 antibody against reelin
During the first 3 days after preparation, 1 µl of CR-50 [100 µg/ml,
diluted in sterile saline; kindly provided by Dr M. Ogawa (see
Ogawa et al., 1995)] was added
to each hippocampal co-culture 3 times a day (n=9).
Biocytin labeling
After 9 DIV, a crystal of biocytin (Sigma, Munich, Germany) was placed onto
the rescued cell layer in slices from the reeler dentate gyrus, or
onto the hilar region of the wild-type mouse, or rat co-culture, in order to
label reeler granule cells and `commissural' projections to the
reeler culture, respectively. After 10 DIV, the cultures were fixed
with 4% paraformaldehyde in 0.1 M phosphate buffer, re-sliced on a Vibratome
(50 µm), and incubated with avidin/biotin peroxidase complex (Vector
Laboratories, Burlingame, CA). Sections were developed with
diaminobenzidine/nickel (DABNi) and counterstained with Cresyl Violet.
Immunocytochemistry
After DIV 7 to 10, the cultures were fixed with 4% paraformaldehyde in 0.1
M phosphate buffer (PB, pH 7.4) for 2 hours. Then the cultures were re-sliced
on a Vibratome (50 µm). Sections were pre-incubated for 30 minutes with
blocking solution (5% normal goat serum, 0.2% Triton-X 100 in 0.1 M PB) at
room temperature. After rinsing in 0.1 M PB, sections were incubated with the
following primary antibodies overnight at 4°C: mouse anti-reelin G10
(1:1000, a generous gift of Dr A. Goffinet), rabbit anti-GFAP (1:500, DAKO,
Denmark), mouse anti-NeuN (Neuron-specific Nuclear Protein; 1:1000, Chemicon,
Hofheim, Germany), mouse anti-calbindin (1:500, Chemicon, Hofheim, Germany),
rabbit anti-calretinin (1:3000, SWant, Bellinzona, Switzerland), goat
anti-calretinin (1:2000, Chemicon, Hofheim, Germany) and rabbit
anti-apolipoprotein E receptor 2 (ApoER2; 1:1000, Santa Cruz Biotechnology,
Heidelberg, Germany). After washing in 0.1 M PB, sections were incubated in
secondary antibodies, Alexa 488 and/or Alexa 568 (1:600, Molecular Probes,
Göttingen, Germany), overnight at 4°C. Some sections were incubated
with Neurotrace (1:1000; Molecular Probes, Göttingen, Germany) for 30
minutes at room temperature. After rinsing in 0.1 M PB for 2 hours, sections
were mounted in Mowiol.
Quantitative analysis of GFAP-positive fibers
GFAP-stained sections were photographed using a confocal microscope (LSM
510, Carl Zeiss, Germany). The length of GFAP-positive fibers was measured by
employing analySIS software (Soft Imaging System GmbH, Münster, Germany).
To estimate the density of GFAP-positive fibers, 3D reconstructions were made
(section thickness, 10 µm; interval, 1 µm). Then the number of
cross-sectioned GFAP-positive fibers per area was determined. The length
density (Lv) was calculated using the formula: Lv=2xN/A (N, number of
cross-sectioned profiles; A, area). Differences were tested for significance
(Student's t-test; P<0.01).
Western blot analysis for reelin
Western blot analysis included lysates of hippocampal tissue from P5 rats
and of slice cultures from rat and reeler hippocampus, and
supernatants of the different incubation conditions.
Brains of P5 rats were removed following decapitation under hypothermic anaesthesia. The hippocampi were prepared and collected in 1.5 ml tubes on ice. The samples were weighed and immediately frozen in liquid nitrogen. Wild-type and reeler hippocampal slices treated with recombinant reelin were incubated for 7 days and then collected in 1.5 ml tubes on ice. The samples were weighed and immediately frozen in liquid nitrogen. Six volumes (v/w) of hypotonic lysis buffer [50 mM Tris, 150 mM NaCl, 5 mM EDTA, 1% protease inhibitor cocktail (Sigma, Munich, Germany), pH 7.6] were added to each sample and the tissue lysed by repeated thawing at 37°C and freezing in liquid nitrogen (five times). After sonication for 5 minutes and trituration with a pipette tip to homogenize larger tissue pieces, the suspension was centrifuged at 20,000 g for 20 minutes (0°C). The resulting crude supernatants were stored at 80°C.
The incubation medium of slice cultures was collected at different time points and stored at 80°C. One microliter recombinant reelin supernatant, 1 µl control supernatant, 1 µl each of the different media, and 6 µl of the supernatants from freshly prepared tissue and slice cultures (6 µl in this case because reelin in tissue and slice cultures was diluted 1:6 during the extraction) were diluted with sample buffer (Invitrogen, Karlsruhe, Germany) and boiled for 5 minutes. Proteins were separated by 3-8% gradient Tris-Acetate gel electrophoresis (SDS-PAGE, Invitrogen, Karlsruhe, Germany) and transferred electrophoretically to polyvinylidene fluoride (PVDF) membranes. A monoclonal antibody against reelin (G10, provided by Dr A. Goffinet) was used as primary antibody at a dilution of 1:3000, followed by an alkaline phosphatase-conjugated secondary antibody (1:10000, Invitrogen, Karlsruhe, Germany). The immunoreaction was visualized by a chemiluminescence reaction (Invitrogen, Karlsruhe, Germany).
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Results |
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A topic effect of wild-type tissue, probably of reelin in the marginal zone of the dentate gyrus, was further confirmed in triplet cultures in which a wild-type culture was placed in between two reeler cultures (Fig. 4). One of the reeler cultures was placed next to the outer molecular layer of the wild-type culture as described above, whereas the other reeler culture was placed next to CA1 in a position remote from the wild-type marginal zone. Whereas the reeler culture next to the wild-type marginal zone formed a compact cell layer, the culture placed next to CA1 retained its loose distribution of neurons all over the dentate area.
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Rescue of radial fiber orientation and granule cell lamination is caused by reelin in the normotopic position
The experiments with wild-type co-cultures suggested an effect of reelin in
the marginal zone of the wild-type culture on the adjacent reeler
slice. In order to test this possibility, we stained these co-cultures with an
antibody against reelin (G10, kindly provided by Dr A. Goffinet, Bruxelles).
In the wild-type culture, reelin-immunoreactive cells were located in the
outer portion of the molecular layer surrounded the band of granule cells
(Fig. 5A). In the
reeler culture, a dense cell layer had only formed in those portions
of the reeler dentate gyrus that were adjacent to the reelin-positive
cells of the wild-type culture, strongly suggesting that this layer formation
in the reeler culture was caused by the juxtapositioned reelin in the
wild-type tissue (Fig.
5A,B).
|
An involvement of reelin in the various experimental approaches described here was confirmed by western blot analysis (Fig. 6). This figure not only shows that reelin is present in fresh hippocampal tissue and in slice cultures from young postnatal rats used for the present rescue experiments (lanes 5, 6), but also demonstrates the presence of reelin in the supernatant of reelin-transfected cells and in reeler slice cultures incubated with this supernatant (lanes 1, 7). Interestingly enough, the concentration of reelin and its fragments appeared higher in the tissue of reeler cultures treated with recombinant reelin than in wild-type cultures (lanes 6, 7). This finding makes it unlikely that the lack of a rescue of granule cell lamination in slice cultures treated with recombinant reelin is due to low reelin concentration. We conclude that reelin is required in its normal topographical position to exert its effects on granule cell lamination.
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Discussion |
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Methodological considerations
The late generation of the granule cells allowed us to use postnatal
hippocampal slices to study layer formation in the dentate gyrus. Many granule
cells are still forming when other types of hippocampal neuron have already
completed their migration and are differentiating their processes and synaptic
connections. Likewise, GFAP-positive cells in the dentate gyrus still show the
characteristics of radial glia, contrasting with the GFAP staining of
astrocytes in the hippocampus proper. Reelin, either added to the medium or
provided by wild-type co-culture, may selectively act on the migration of
granule cells in these postnatal cultures. In fact, we did not find an effect
on early generated pyramidal neurons and mossy cells, and observed a rescue of
granule cell lamination only in reeler slices from P0-P2, and not in
slices from later stages. These specific experimental conditions do not allow
us to generalize our results, and it remains open as to what extent the
present findings can be extrapolated to other brain regions and to other
developmental stages. Unlike the present results, incubation of slices from
embryonic reeler neocortex in the presence of recombinant reelin
partially rescued the reeler phenotype
(Jossin et al., 2004), as did
heterotopic reelin expression (Magdaleno
et al., 2002
).
Reelin acts on GFAP-positive radial glial fibers in the dentate gyrus
We recently demonstrated that Dab1, a cytoplasmic adapter protein of the
reelin signaling cascade, is expressed by GFAP-positive radial glial cells in
the dentate gyrus (Förster et al.,
2002). Moreover, we were able to show that GFAP-positive radial
glial cells responded to reelin in the stripe choice assay
(Förster et al., 2002
;
Frotscher et al., 2003
). In
reeler mice, as well as in mutants lacking the reelin receptors
apolipoprotein E receptor 2 (ApoER2) and/or very low density lipoprotein
receptor (VLDLR), and in scrambler mice lacking Dab1, there were
severe malformations of the radial glial scaffold in the dentate gyrus
(Weiss et al., 2003
). Although
together these findings suggested an effect of reelin on GFAP-positive radial
glial fibers in the dentate gyrus, which is mediated via lipoprotein receptors
and Dab1, the nature of this effect remained unclear.
Our present results clearly show that reelin increases the length of
GFAP-positive fibers in the dentate gyrus, an effect that was also observed in
neocortical radial glial cells, but not radial glial cells from the basal
ganglia (Hartfuss et al.,
2003). In reeler mutants, GFAP-positive cells show
morphological characteristics of astrocytes, suggesting a premature
transformation of radial glial cells. Reelin added to the medium seems to
prevent this premature astroglial differentiation. By increasing the length of
GFAP-positive fibers, reelin may maintain a radial glial scaffold in the
postnatal dentate gyrus, thereby supporting the migration of postnatally
generated granule cells. Lack of reelin in the reeler mutant would
then result in a premature astrocytic differentiation and an altered granule
cell migration, with many granule cells remaining near their site of
generation in the hilus.
Reelin is required in a normotopic position to exert its function on granule cell migration
It is a major finding of the present study that reelin in the medium does
not rescue layer formation in the reeler dentate gyrus. Granule cells
in reeler cultures treated with recombinant reelin were scattered all
over the dentate area. Our results also show that ubiquitous reelin, while
increasing the length of glial processes, does not result in the formation of
a regular radial glial scaffold. In wild type, radial glial fibers extend from
the subgranular zone to the pial surface, thereby traversing the granule cell
layer perpendicularly. Such a regular radial glial orientation was only
achieved in the present experiments when a reeler slice was
co-cultured with a wild-type slice with the wild-type marginal zone in close
apposition. Moreover, only under these conditions did we observe the formation
of a granule cell layer. Our findings suggest that reelin is required in a
normotopic position for the directed growth of radial glial fibers, which form
a regular scaffold suitable for granule cell migration and lamination
(Fig. 9).
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Previous studies suggested that reelin acts on neurons directly, by
functioning as a stop signal (Curran and
D'Arcangelo, 1998; Frotscher,
1998
). Forming a component of the extracellular matrix in the
marginal zone (the future layer I of the cortex), reelin seems to stop neurons
in their migration, resulting in a cell-poor layer I in wild-type animals.
Recent studies indicate that this effect may be brought about by the
phosphorylation of Dab1 at Tyr220 and Tyr232, which appears to be important
for the detachment of the neuron from the radial glial fiber
(Sanada et al., 2004
). In
reeler mice and Dab1 mutants, layer I is densely filled with
neurons, and these recent findings suggest that the detachment from the radial
glial fiber is severely altered in these animals. Like layer I of the
neocortex, the molecular layer of the dentate gyrus, the marginal zone of this
brain region, is a cell-poor layer with the granule cells accumulating
underneath. Like in the marginal zone of the neocortex, reelin in the outer
molecular layer of the dentate gyrus may directly act on granule cells by
stopping their migration and initiating their detachment from the radial fiber
by the phosphorylation of Dab1 (Sanada et
al., 2004
). In fact, in our rescue experiments with wild-type
co-cultures, we regularly observed a zone that was almost free of granule
cells in the reeler tissue directly attached to the wild-type
marginal zone (e.g. Fig. 3D,
Fig. 4), suggesting that reelin
does function as a stop signal for the migrating granule cells in the
reeler tissue under these experimental conditions. Arrest of
migration eventually leads to the accumulation of granule cells in a densely
packed granular layer (Fig. 9).
Alternatively, granule cell precursors, i.e. radial glial cells, may migrate
by soma translocation and retract their basal (hilar) processes
(Miyata et al., 2001
). In this
scenario, we would have to assume that reelin stops soma translocation
(Fig. 9). Further studies are
required to clarify precisely how granule cells migrate from their site of
origin in the secondary proliferation zone of the hilar region to the granule
cell layer.
Rescue of granule cell polarity and orientation
The uniform bipolar morphology and parallel alignment of granule cells in
the wild-type dentate gyrus is largely lost in reeler mutants, and in
mutants lacking VLDLR and ApoER2
(Stanfield and Cowan, 1979;
Drakew et al., 2002
;
Gebhardt et al., 2002
). We
noticed a remarkable rescue of dendritic orientation in reeler
sections co-cultured with wild type. Rescue of granule cell lamination and
dendritic orientation were paralleled by a normalization of the laminated
termination of commissural axons, indicating the presence of positional cues
for these fibers on granule cell dendrites
(Zhao et al., 2003
). It
remains to be analyzed in detail whether or not this re-direction of granule
cell dendrites towards the pial surface is a direct effect of reelin on
dendritic growth, similar to its effect on radial glia fiber orientation.
Assuming that radial glial cells are precursors of neurons
(Malatesta et al., 2000
;
Miyata et al., 2001
;
Noctor et al., 2001
), the
radial fiber may be inherited by the neuron and become its apical dendrite. If
this scenario holds true for dentate granule cells, then the normalized
dendritic orientation would simply result from the rescue of radial fiber
orientation. Alternatively, reelin may act on dendritic orientation and
branching directly (Niu et al.,
2004
), similar to its effects on radial fibers and axon terminals
(del Rio et al., 1997
). With
the different effects of reelin described in the present study, and the
recently discovered effects of reelin on chain migration
(Hack et al., 2002
) and
synaptic plasticity (Weeber et al.,
2002
), we are beginning to unveil the diverse functions of this
molecule.
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ACKNOWLEDGMENTS |
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