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Volume 17, Number 1,
Issue of January 1, 1997
pp. 23-31
Copyright ©1997 Society for Neuroscience
Reelin Is a Secreted Glycoprotein Recognized by the CR-50
Monoclonal Antibody
Gabriella D'Arcangelo1,
Kazunori Nakajima1, 2,
Takaki Miyata2, 3,
Masaharu Ogawa3,
Katsuhiko Mikoshiba2, 4, and
Tom Curran1
1 Department of Developmental Neurobiology, St. Jude
Children's Research Hospital, Memphis, Tennessee 38105, 2 Molecular Neurobiology Laboratory, Tsukuba Life Science
Center, The Institute of Physical and Chemical Research (RIKEN),
Tsukuba, Ibaraki 305, Japan, 3 Department of Physiology,
Kochi Medical School, Nankoku, Kochi 783, Japan, and
4 Department of Molecular Neurobiology, Institute of
Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
The neurological mouse mutant strain reeler displays
abnormal laminar organization of several brain structures as a
consequence of a defect in cell migration during neurodevelopment. This
phenotype is a result of the disruption of reelin, a
gene encoding a protein that has several structural characteristics of
extracellular matrix proteins. To understand the molecular basis of the
action of Reelin on neuronal migration, we constructed a full-length
reelin clone and used it to direct Reelin expression.
Here, we demonstrate that Reelin is a secreted glycoprotein and that a
highly charged C-terminal region is essential for secretion. In
addition, we demonstrate that an amino acid sequence present in the
N-terminal region of Reelin contains an epitope that is recognized by
the CR-50 monoclonal antibody. CR-50 was raised against an antigen expressed in normal mouse brain that is absent in reeler
mice. The interaction of CR-50 with its epitope leads to the disruption of neural cell aggregation in vitro. Here, we used CR-50
to precipitate Reelin from reticulocyte extracts programmed with
reelin mRNA, from cells transfected with
reelin clones, and from cerebellar explants. The
reelin gene product seems to function as an instructive signal in the regulation of neuronal migration.
Key words:
reeler;
cerebral cortex;
cerebellum;
extracellular matrix;
glycosylation;
mutant mice;
neuronal
migration
INTRODUCTION
reeler (rl) is a mouse
autosomal recessive mutation that affects the organization of the
developing brain (Caviness and Rakic, 1978
; Goffinet, 1984; Rakic and
Caviness, 1995). The most striking aspects of the reeler
phenotype are the abnormal positioning of neurons throughout the
cerebral cortex, the cerebellum, and the hippocampus and the aberrant
orientation of cell bodies and fibers. In the cerebral cortex of
reeler mice, neurons generated early in development,
normally destined to form the subplate, occupy ectopic positions in
superficial cortical layers. Neurons generated at later stages,
destined to form the cortical plate, migrate radially but fail to
bypass previously generated neurons. Thus, the pattern of neocortical
histogenesis in reeler mice seems to be inverted. The
reeler cerebellum is considerably smaller than normal, and
it lacks foliation and a Purkinje cell layer (Mariani et al., 1977;
Mikoshiba et al., 1980; Goffinet et al., 1984). Neurons positioned
abnormally also are encountered in the hippocampus (Caviness, 1973;
Stanfield and Cowan, 1979). Although neurogenesis and neuronal
connectivity primarily are preserved, brain function is impaired in
reeler mice, and they exhibit severe motor defects, including tremors, ataxia, and difficulty in balance and locomotion (Falconer, 1951).
Neuroanatomical analysis suggested that the gene affected by the
reeler mutation is critical for the appropriate migration of
postmitotic neurons (Goffinet, 1984; Caviness et al., 1988). The recent
cloning of reelin, the gene mutated in reeler
mice (D'Arcangelo et al., 1995), has provided new insights into the molecular mechanisms underlying the reeler defects
(Goffinet, 1995; Rakic and Caviness, 1995; Rugarli and Ballabio, 1995).
reelin encodes a protein of 3461 amino acids with several
features of extracellular molecules, including a cleavable signal
peptide, several potential glycosylation sites, and EGF-like
repeats.
In two strains of reeler, rl (Falconer, 1951) and
rltg (Miao et al., 1994), no reelin
mRNA was detected (D'Arcangelo et al., 1995). The defect in
rl originates from a 150 kb deletion in the reelin gene (Bar et al., 1995; D'Arcangelo et al., 1995),
whereas in rltg it arises from an intragenic
deletion of reelin sequences associated with the insertion
of a transgene (Miao et al., 1994; D'Arcangelo et al., 1995). In a
third strain, rlorl (Guenet, 1981), a small
deletion in reelin was described that affects the 3
end of
the coding sequence (Curran et al., 1995; Hirotsune et al., 1995). This
deletion results from exon skipping as a consequence of the
transposition of an active L1 sequence into the gene (Takahara et al.,
1996).
In situ hybridization studies revealed that
reelin is expressed in a complex pattern during
neurodevelopment (D'Arcangelo et al., 1995). In the embryonic cerebral
cortex, reelin mRNA is expressed specifically by a subset of
neurons in the most superficial layer, the Cajal-Retzius cells, which
are among the first neurons to differentiate in the brain
(Marin-Padilla and Marin-Padilla, 1982; Derer and Derer, 1990;
D'Arcangelo et al., 1995; Hirotsune et al., 1995). In the cerebellum,
reelin mRNA is expressed very highly in the granule cell
layers (D'Arcangelo et al., 1995).
The distribution of reelin mRNA is very similar to that
recently reported for an epitope recognized by the CR-50 monoclonal antibody. Generated by immunizing reeler mice with normal
brain homogenate, this antibody interferes with the pattern of
aggregation of neocortical cells in vitro (Ogawa et al.,
1995). In the present study, we generated full-length and truncated
reelin cDNA clones to investigate the biochemical properties
of Reelin and its relationship to the CR-50 epitope.
MATERIALS AND METHODS
Construction of reelin clones. The entire
reelin open reading frame was assembled by fusing five
overlapping cDNA clones isolated previously (D'Arcangelo et al., 1995)
and subcloning them into the vector pcDNA3 (Invitrogen, San Diego, CA).
This vector allows mammalian expression from the human cytomegalovirus
(CMV) promoter or in vitro transcription from the T7
promoter. The following reelin fragments were used: 1.2 kb
NaeI-SalI from p5BS1, 1.3 kb
SalI-NdeI from pBS2, 3.1 kb
NdeI-BspEI from pBS6, 770 bp
BspEI-ApaLI from p3Rea3, and 4.2 kb
ApaLI-EcoRV from pBS53. The final clone (pCrl)
contains the entire reelin open reading frame (10,383 bp) plus 95 bp of sequence 5 to the initiator methionine codon and 82 bp
of 3 untranslated sequence (reelin cDNA nucleotides
188-10,748). To produce an epitope-tagged version of Reelin (pCrlM),
we annealed oligonucleotides encoding the human c-Myc epitope 9E10
(QKLISEEDLN) flanked by BspEI restriction site sequences and
inserted them, in frame, into the unique BspEI site present
in pCrl. To generate a truncated pCrl3328 clone lacking the C terminus,
we eliminated a 500 bp XhoI fragment from pCrl. Other
expression constructs contain reelin cDNA nucleotides
188-865 (pCrl194), 188-1029 (pCrl250), 188-1505 (pCrl407), and
188-1664 (pCrl462) cloned into pcDNA3. pCrl1837 is similar to pCrlM
except for the orientation of the c-Myc epitope in the BspEI
site, which is inverted, thus creating a stop codon immediately after
nucleotide 5789. The nucleotide sequence of reelin has been
deposited in GenBank; the accession number is U24703[GenBank].
In vitro transcription/translation. Expression plasmids
were transcribed, and the resulting RNA was translated in
vitro via a reticulocyte lysate transcription/translation system
according to the manufacturer's instructions (TnT, Promega, Madison,
WI). DNA (2 µg) was transcribed in a 50 µl reaction mix with T7 RNA polymerase. Translation was performed in the presence of 40 µCi of
[35S]methionine or a mix of [35S]methionine
and [35S]cysteine in the absence of unlabeled methionine.
One microliter of the reaction mix was diluted in 100 µl of SDS
sample buffer and subjected to SDS-PAGE. The remainder of the reaction
mix was diluted in RIPA buffer (50 mM Tris, pH 8, 150 mM NaCl, 1% Nonidet P40, 0.5% Na deoxycholate, and 0.1%
SDS) for immunoprecipitation analysis.
COS cell transfection. COS-7 cells (4 × 105) were plated in 60 mm dishes in the presence of 5 ml of
DMEM (BioWhittaker, Walkersville, MD) supplemented with 10% fetal
bovine serum (Life Technologies, Gaithersburg, MD) and incubated
overnight. On the next day, the medium was replaced with Opti-MEM (Life
Technologies), and the cells were transfected with the LipofectAMINE
reagent (Life Technologies) according to the manufacturer's
instructions. After 5-7 hr of transfection in 2 ml of Opti-MEM, 2 ml
of DMEM containing 20% fetal bovine serum was added, and the cultures
were incubated overnight. On the next day, the medium was replaced with
fresh DMEM containing 10% serum. After one additional day, cells were examined by immunofluorescence analysis, or they were prepared for
immunoprecipitation analysis as described below.
Cerebellar primary cultures. The cerebellum was removed by
dissection from postnatal day 5-8 (P5-P8) normal or reeler
B6C3Fe mice, which were generated as the progeny of a rl
heterozygous cross (Jackson Laboratory, Bar Harbor, ME). Then the
tissue was chopped finely with a razor blade and triturated in a
plastic pipette. Cells were resuspended in basal Eagle's medium
supplemented as described (Fischer, 1982), with 5% horse serum
(HyClone, Logan, UT). Explants or dispersed cells (2 × 105 cells/cm2) were plated in tissue culture
dishes that had been precoated with 20 µg/ml
poly-L-lysine. The cultures were switched to serum-free medium 1 d after plating and incubated for 1-4 d. Extensive
neurite outgrowth during this period was indicative of healthy
cultures.
Immunoprecipitation. Reelin was produced in vitro
using rabbit reticulocyte lysates in the presence of
[35S]methionine or a mix of [35S]methionine
and [35S]cysteine (Amersham, Arlington Heights, IL, or
New England Nuclear, Boston, MA) in the absence of unlabeled
methionine. The transcription/translation reaction was diluted in 1 ml
of RIPA buffer supplemented with the protease inhibitors leupeptin (20 µg/ml), aprotinin (0.1 mg/ml), and phenylmethylsulfonyl fluoride
(PMSF; 2 mM). Aliquots of the diluted mixture were used for
immunoprecipitation. To prepare radiolabeled Reelin expressed in COS
cells, we incubated cultures overnight in DMEM lacking methionine and
cysteine, supplemented with 1% fetal bovine serum and 300 µCi/ml of
a mix of [35S]methionine and [35S]cysteine.
Reelin expressed in cerebellar cultures was labeled overnight with the
[35S] labeling mix in basal Eagle's medium depleted of
methionine (Cellgro) and supplemented as previously described (Fischer,
1982). For immunoprecipitation analysis, culture medium was collected from COS or cerebellar cells and diluted 1:1 with 2× RIPA buffer. Cell
extracts were prepared in RIPA buffer supplemented with protease inhibitors as described above. Both supernatants and lysates were precleared by centrifugation at 1500 rpm in a refrigerated Eppendorf microfuge for 10 min.
Anti-Myc monoclonal antibody 9E10 (a gift of G. I. Evan, Imperial
Cancer Research Fund, London, UK, and M. J. Bishop, University of
California, San Francisco, CA, or obtained commercially, Babco, Richmond, CA), CR-50 ascites (Ogawa et al., 1995), rabbit antisera anti-Rlp3 raised against amino acids 1144-1163 of Reelin, or
affinity-purified rabbit antibody anti-rp5 raised against amino acids
3443-3461 of Reelin were added to the samples and incubated at 4°C
for 2 hr to overnight. Immobilized G-protein agarose beads (Immunopure plus, Pierce, Rockford, IL) were added to precipitate the antibodies, and the samples were incubated for an additional 30 min.
Immunoprecipitates were collected by centrifugation and washed three
times with RIPA buffer. Samples were resuspended in 20 µl of SDS
sample buffer, boiled, and loaded onto SDS polyacrylamide gels (4-12%
gradient gels, Novex, San Diego, CA, or 4% Duracryl, Oxford
Glycosystems, Abingdon, UK).
Glycosylation analysis. Immunoprecipitates were resuspended
in the appropriate glycosidase buffer and digested as follows. For
peptide-N-glycosidase F (PNGaseF) digestion, samples were resuspended in 2× PNGaseF buffer (100 mM potassium
phosphate, pH 7, 0.4% SDS, and 2% 
-mercaptoethanol) and boiled for
5 min. The concentration of Nonidet P-40 was adjusted so that it
exceeded SDS by sevenfold in a 20 µl reaction mix. The sample was
divided into two aliquots, and PNGaseF (0.2 U, Boehringer Mannheim,
Indianapolis, IN) was added to one tube. For neuraminidase digestion,
samples were resuspended in 2× neuraminidase buffer (200 mM sodium acetate, pH 5.5, 0.5% SDS, and 0.7%
-mercaptoethanol) and boiled for 5 min. The concentration of Nonidet
P-40 was adjusted so that it exceeded SDS by sevenfold in a 20 µl
reaction mix. The sample was divided and neuraminidase from
Clostridium perfringens (1 µl of NeuA, Worthington,
Freehold, NJ) was added to one tube. For O-glycosidase,
samples were resuspended in 50 mM sodium phosphate, pH 5, and O-glycosidase DS (1 mU, Glyko, Novato, CA) was added to
one sample. For chondroitinase ABC digestion, samples were resuspended
in 20 mM Tris HCl and 40 mM sodium acetate, pH
8; chondroitinase ABC (10 mU, Boehringer Mannheim) was added to one sample. All samples were incubated for 1 hr at 37°C. After
incubation, an equal volume of 2× SDS sample buffer was added to each,
and the samples were boiled and loaded onto 4% SDS-polyacrylamide.
Immunofluorescence. COS cells were transfected and plated on
glass slide chambers (Nunc, Naperville, IL). Two days after
transfection, cells were rinsed with PBS, fixed with 2%
paraformaldehyde, and permeabilized with 1% Triton X-100. Primary
mouse monoclonal antibodies 9E10 (anti-Myc) or CR-50 ascites were
diluted 1:200 in PBS containing 2.5% normal horse serum (Vector
Laboratories, Burlingame, CA). Cells were incubated with the primary
antibody for 1-2 hr at room temperature and then washed and incubated
for 30 min with the secondary antibody, FITC-labeled rabbit anti-mouse
(Dako, Carpenteria, CA), diluted 1:80 as described above. Cells were
rinsed twice with PBS before mounting on coverslips with fluorescence
mounting medium (Vectashield, Vector Laboratories). The staining was
analyzed under a microscope with phase-contrast and fluorescence
settings (BX60, Olympus Optical, Tokyo, Japan).
RESULTS
Generation of reelin clones
To facilitate the investigation of Reelin function, we assembled a
full-length reelin construct by the consecutive cloning of
five contiguous cDNAs, as described in Materials and Methods. The
full-length construct contains 95 bp of sequence 5 to the initiator
methionine codon and 82 bp of 3 untranslated sequence. The open
reading frame of 10,383 bp is sufficient to encode a protein of 3461 amino acids. After cleavage of the signal peptide, the molecular mass
of Reelin was predicted to be ~385 kDa. The full-length open reading
frame was placed under the control of the CMV promoter for expression
in mammalian cells (pCrl, Fig. 1). This vector also
contains a promoter sequence for the T7 RNA polymerase, which allows
transcription in vitro. To facilitate detection of the
recombinant protein, we inserted a short DNA sequence encoding a human
c-Myc epitope in frame in the fourth Reelin repeat, as illustrated
(pCrlM, Fig. 1).
Fig. 1.
Assembly of full-length and truncated
reelin cDNAs. Five overlapping plasmids
(lines) encoding portions of the reelin
cDNA (p5BS1, pBS2, pBS6, p3Rea3, and pBS53) were digested with the indicated restriction enzymes and cloned consecutively into pcDNA3 to
generate a full-length clone that contains the entire open reading
frame under the control of the mammalian CMV and the bacteriophage T7
promoters (pCrl). The initiator methionine
codon (Met) and the stop codon (Stop) are
indicated. After signal peptide cleavage, the full-length protein
(box) is predicted to be 385 kDa in size. EGF-like
repeats (E, black boxes) and a highly
positively charged region in the C terminus (++) are indicated. A
double-stranded oligonucleotide encoding a c-Myc epitope, 9E10
(c-Myc), was cloned in frame into the unique
BspEI restriction site of pCrl to generate the pCrlM
construct. Other expression constructs (lines) encoding truncated Reelin proteins in pcDNA3 are shown below the
protein diagram. The numbers contained in the expression
construct names refer to the last encoded amino acid of Reelin. The
pCrl1837 contains an inverted c-Myc oligonucleotide at the
BspEI restriction site, which puts the C-terminal half
of the protein out of frame (dotted line).
[View Larger Version of this Image (16K GIF file)]
Several truncated clones expressing portions of the Reelin sequence
also were generated. These contain truncations at amino acid 194 (pCrl194), 250 (pCrl250), 407 (pCrl407), 462 (pCrl462), 1837 (pCrl1837), and 3328 (pCrl3328), as illustrated in Figure 1.
The CR-50 monoclonal antibody recognizes Reelin
The staining pattern of CR-50, a monoclonal alloantibody raised in
reeler mice against normal brain homogenate (Ogawa et al., 1995), is very similar to the distribution of reelin mRNA.
Furthermore, this antibody interferes with the pattern of aggregation
of neocortical cells in vitro (Ogawa et al., 1995). To
determine whether CR-50 recognizes Reelin, we expressed the full-length
reelin construct containing a c-Myc epitope (pCrlM) in
vitro, using a coupled transcription/translation system. Reelin
was detected as a single polypeptide of ~385 kDa on
SDS-polyacrylamide gels. It was immunoprecipitated by CR-50, as well as
by antibodies specific for the c-Myc epitope, and by antibodies raised
against amino acids 1144-1163 of Reelin (Rlp3; Fig. 2,
lanes 2-4). In contrast, no Reelin was precipitated
in the absence of antibodies or by preimmune sera (Fig. 2, lanes 1, 5). This suggests that the epitope recognized by CR-50 is
encoded by the primary amino acid sequence of Reelin, because many
post-translational modifications, such as glycosylation, do not occur
in the reticulocyte lysate.
Fig. 2.
Expression of full-length Reelin in
vitro. A plasmid encoding full-length Myc-tagged Reelin (pCrlM)
was transcribed in vitro by the T7 RNA polymerase and
translated by using a rabbit reticulocyte lysate. The
[35S]-labeled final product was analyzed on a 4-12%
SDS-polyacrylamide gel. Aliquots of the reaction were treated with no
antibody (lane 1), monoclonal antibody against c-Myc
(9E10, lane 2), monoclonal antibody CR-50 (lane
3), polyclonal anti-Reelin peptide Rlp3 (lane 4), or preimmune serum (lane 5). The
immunoprecipitated Reelin protein is ~385 kDa.
[View Larger Version of this Image (52K GIF file)]
Immunocytochemistry was used to confirm the finding that CR-50
recognizes Reelin. CR-50 was used previously to demonstrate the
presence of a reeler-related antigen in brain sections and in cultured neurons (Ogawa et al., 1995; Miyata et al., 1996). COS
cells were transfected with or without pCrlM, fixed, and incubated with
CR-50, as described in Materials and Methods. After incubation with
FITC-labeled secondary antibody, positive cells were visualized under a
fluorescent microscope. Approximately 5% of the cells transfected with
pCrl revealed a strong intracellular signal (Fig. 3),
whereas no signal was detected in cells transfected in the absence of
pCrl (data not shown), demonstrating the specificity of CR-50 for
Reelin. The CR-50 staining pattern, which was particularly intense near
the nucleus, was similar to that obtained with the anti-Myc antibody
(data not shown).
Fig. 3.
Intracellular localization of Reelin in COS cells.
After transfection with pCrlM encoding full-length Reelin under the
control of the CMV promoter, COS cells were fixed, permeabilized, and incubated for 1 hr with the primary CR-50 antibody and for an additional 30 min with FITC-tagged anti-mouse secondary antibody. A, Fluorescent image of a cell expressing Reelin (80×
magnification). B, Phase-contrast image of the same cell
field.
[View Larger Version of this Image (73K GIF file)]
CR-50 recognizes the N terminus of Reelin
To map the CR-50 epitope on Reelin, we used a series of truncated
reelin expression clones (Fig. 1) in an in vitro
transcription/translation assay. Each construct encoded a truncated
Reelin protein of the expected size (Fig.
4A), which was subjected to
immunoprecipitation with the CR-50 antibody. As for full-length Reelin
(Fig. 2, lane 3), the CR-50 antibody was able, specifically,
to immunoprecipitate truncated proteins containing amino acids 1-1837
(pCrl1837), 1-462 (pCrl462), and 1-407 (pCrl407), but not proteins
containing only amino acids 1-194 (pCrl194) or 1-250 (pCrl250) (Fig.
4B). No appreciable signal was detected when a
control IgG antibody used for immunoprecipitation (data not shown).
These data demonstrate that the CR-50 epitope is located between Reelin
amino acids 251 and 407.
Fig. 4.
CR-50 epitope mapping. Plasmids encoding truncated
Reelin proteins were transcribed in vitro by the T7 RNA
polymerase and translated by using a rabbit reticulocyte lysate in the
presence of [35S]methionine and
[35S]cysteine. A, The products of pCrl1837
(206 kDa, lane 1), pCrl462 (51 kDa, lane
2), pCrl407 (46 kDa, lane 3), pCrl250 (27.5 kDa, lane 4), and pCrl194 (22 kDa, lane
5) were analyzed on a 4-12% SDS-polyacrylamide gel.
B, The same in vitro translated proteins as in A were subjected to immunoprecipitation with the
monoclonal antibody CR-50 and analyzed on a 4-12% SDS-polyacrylamide
gel. Because all truncated proteins except those encoded by pCrl194 and
pCrl250 are recognized by CR-50, the epitope is located between amino
acids 251 and 407 of Reelin.
[View Larger Version of this Image (51K GIF file)]
Reelin is a secreted glycoprotein
Analysis of the phenotype of reeler mice led to the
proposal that they lack a signaling molecule required for the
regulation of cellular interactions during neuronal migration. This was
confirmed and extended by studies using chimeric reeler and
normal mice, which demonstrated that at least some Purkinje cells from
reeler mice are able to differentiate properly when exposed
to a normal cerebellar environment (Terashima et al., 1986). One
interpretation of these data is that the reeler gene encodes
a protein that provides an extrinsic signal for migrating neurons. This
is consistent with the predicted amino acid sequence of Reelin, which
indicates the presence of a cleavable signal peptide at the N terminus. This feature, together with the sequence similarity to F-spondin and
the presence of EGF-like repeats, suggests that Reelin is a secreted
protein. To investigate this possibility formally, we looked for the
presence of secreted Reelin in medium from COS cells expressing pCrlM
and in medium from cerebellar explants.
COS cell cultures were labeled overnight with a mixture of
[35S]methionine and [35S]cysteine, as
described in Materials and Methods. Media were collected and processed
for immunoprecipitation with antibodies directed against the c-Myc
epitope (Fig. 5A) and CR-50 (Fig.
5B). A c-Myc antibody specifically precipitated Reelin
(~400 kDa) from the medium obtained from COS cells transfected with
pCrlM (Fig. 5A, lanes 3, 4), but not from that
obtained from control cultures (Fig. 5A, lanes 1, 2).
Similarly, CR-50 specifically precipitated Reelin from the medium of
transfected COS cells (Fig. 5B, lanes 1-4). Other protein bands were detected occasionally in
immunoprecipitation assays; however, these represent either
cross-reacting cellular proteins or degradation products of Reelin. To
analyze the expression of endogenous Reelin, we prepared cultures from
developing cerebelli dissected at P5-P8. After 1-4 d in culture,
cells were labeled biosynthetically with [35S]methionine
and [35S]cysteine. Reelin (~400 kDa) was clearly
detected both in CR-50 immunoprecipitates from the culture medium and
from cell extracts of cultured cerebellum (Fig. 5B,
lanes 5, 6). Additional bands may correspond to
Reelin proteolytic fragments or may result from antibody
cross-reactivity. The size of Reelin produced by cerebellar cells was
similar to that of the protein synthesized in COS cells. Immunoprecipitated Reelin produced by COS or cerebellar cells migrated
at a higher apparent molecular weight than that expressed in
vitro in reticulocyte extracts, which is predicted to be ~385 kDa (Fig. 5A,B, lanes 5, 7, respectively). This suggests that Reelin undergoes
post-translational modification in intact cells. These data confirm the
finding that CR-50 recognizes Reelin specifically, and they demonstrate
that Reelin is a secreted protein that is post-translationally
modified.
Fig. 5.
Reelin is modified and secreted by COS or
cerebellar cells. A, COS cells (lanes
1-4) were transfected with (lanes 3, 4) or without (lanes 1, 2)
pCrlM. The [35S]-labeled
supernatant was subjected to immunoprecipitation with no antibody
(lanes 1, 3) or with anti-Myc antibody 9E10
(lanes 2, 4). A specific band of ~400 kDa
(top arrowhead) was detected only in the sample
containing both pCrlM and anti-Myc. The predicted 385 kDa in
vitro translated [35S]-labeled product of pCrlM
was immunoprecipitated with the anti-Myc antibody (lane
5). The protein produced in vitro (bottom
arrowhead) seems to have a lower molecular mass than that
obtained in COS cells. B, The supernatant from COS cells
transfected with no DNA (lanes 1, 2) or pCrlM
(lanes 3, 4), cerebellar cell supernatant (lane 5) or cerebellar cell lysates (lane
6), and in vitro translation reaction of
pCrlM (lane 7) were labeled with
[35S], as described in Materials and Methods, and
subjected to immunoprecipitation with the CR-50 antibody. All
immunoprecipitates from transfected COS or cerebellar cells migrated at
a higher apparent molecular weight (top arrowhead) than
the in vitro translated product (bottom arrowhead). The position of a 220 kDa molecular weight marker is indicated.
[View Larger Version of this Image (42K GIF file)]
So that the nature of the post-translational modifications of Reelin
that result in an apparent increase in molecular weight might be
investigated, CR-50 immunoprecipitates from transfected COS cell medium
and from medium removed from cerebellar explants were digested with a
series of glycosidases, and the products were analyzed by SDS-PAGE.
CR-50 immunoprecipitated Reelin from the medium of COS cells
transfected with pCrlM (Fig. 6A, lanes 2-10), but not from the medium obtained from mock-transfected cells (Fig. 6A, lane 1). After digestion with
PNGaseF, an enzyme that specifically cleaves asparagine-linked
N-glycans, the apparent molecular mass of Reelin was reduced (Fig.
6A, compare lanes 3 and
4). Digestion with O-glycosidase, an
enzyme that cleaves O-linked carbohydrate chains attached to serine and
threonine residues, resulted in a modest decrease in the apparent mass
of Reelin (Fig. 6A, lanes 5, 6). No appreciable effect was observed after digestion with
neuraminidase A (Fig. 6A, lanes 7,
8), which cleaves sialic acid groups, or with chondroitinase
ABC (Fig. 6A, lanes 9,
10), which cleaves chondroitin sulfate and dermatan sulfate
side chains from proteoglycans. CR-50 also precipitated the endogenous
Reelin from the medium of cerebellum explants obtained from normal mice (Fig. 6B, lanes 2-5), but not from explants obtained
from reeler mice (Fig. 6B, lane 1).
Treatment with PNGaseF (Fig. 6B, lane 3) and, to a
lesser extent, O-glycosidase (Fig. 6B,
lane 5) resulted in an apparent size reduction, whereas
neuraminidase A (Fig. 6B, lane 4) had no
effect. These data indicate that Reelin is subject to N-linked and, to
a lesser extent, to O-linked glycosylation.
Fig. 6.
Reelin is glycosylated. A, COS
cells were transfected with no DNA (lane 1) or with
pCrlM (lanes 2-10). Cells were labeled with
[35S], and Reelin was immunoprecipitated from the
supernatant with the CR-50 antibody. Immunocomplexes were resuspended
in gel loading buffer (lanes 1, 2) or in the appropriate
glycosidase buffer and incubated with (lane 4) or
without (lane 3) PNGaseF, with (lane 6) or without (lane 5)
O-glycosidase, with (lane 8) or without (lane 7) neuraminidase A, and with (lane
10) or without (lane 9) chondroitinase ABC.
After digestion, gel loading buffer was added, and the samples were
analyzed on a 4% SDS polyacrylamide gel. B, Cerebellar
cells were obtained from postnatal day 7 reeler (lane 1) or normal (lanes 2-5) mice.
Cells were labeled with [35S], and Reelin was
immunoprecipitated from the supernatant with the CR-50 antibody.
Immunocomplexes were resuspended in gel loading buffer (lanes 1, 2) or in the appropriate glycosidase buffer and digested with
PNGaseF (lane 3), neuraminidase A (lane
4), or O-glycosidase (lane
5). Samples were analyzed on a 4% SDS polyacrylamide
gel.
[View Larger Version of this Image (42K GIF file)]
The C terminus of Reelin is required for secretion
Several independent alleles of the reeler mutation have
been described. In two strains, rl (Falconer, 1951) and
rltg (Miao et al., 1994), the mutation is a
consequence of a relatively large deletion of reelin, which
results in a complete loss of expression (Bar et al., 1995;
D'Arcangelo et al., 1995). In contrast, mice of the
rlorl strain (Guenet, 1981) have a small
deletion of a 220 bp exon near the 3 end of reelin, which
results in a frame shift in the C terminus of Reelin (Curran et al.,
1995; Hirotsune et al., 1995; Takahara et al., 1996). The predicted
protein product of the rlorl gene lacks 205 C-terminal amino acids and contains 70 novel amino acids from an
out-of-frame region. Reverse transcription-polymerase chain reaction
(RT-PCR) analysis indicated that reelin mRNA is present in
rlorl mice (Hirotsune et al., 1995), suggesting
that the protein also might be present. We noted that the region of
Reelin mutated in rlorl contains a short
C-terminal region with a very high positive charge that might be
required for the function of Reelin. Therefore, we created a truncated
version of reelin (pCrl3328) lacking a region encoding 133 C-terminal amino acids, which includes this highly charged domain. We
confirmed the truncation in the product of this construct with
affinity-purified anti-rp5 antibodies directed against C-terminal amino
acids 3443-3461 of Reelin. As expected, the anti-rp5 antibodies
precipitated Reelin from extracts of COS cells transfected with
full-length Reelin (pCrlM), but not from cells transfected with
pCrl3328 or from untransfected cells (Fig. 7,
lanes 1-3). Bands smaller than 400 kDa are attributable to antibody cross-reactivity. Furthermore, we confirmed that COS cells
express high levels of pCrl3328 by immunofluorescence analysis with the
CR-50 antibody, which recognizes an N-terminal epitope (data not
shown). When the CR-50 antibody was used in the immunoprecipitation assay, both full-length and truncated Reelin were precipitated from
extracts of transfected cells (Fig. 7, lanes 4-6).
CR-50 also precipitated full-length Reelin from transfected cell
supernatants; however, it failed to precipitate the truncated protein
(Fig. 7, lanes 7-9). These data demonstrate that the highly
charged C terminus of Reelin is required for secretion. Because this
region is missing in rlorl, we suggest that the
reeler phenotype is a consequence of the absence of
extracellular Reelin.
Fig. 7.
The C terminus of Reelin is required for
secretion. COS cells were transfected with no DNA (lanes 1, 4, 7), pCrlM (lanes 2, 5, 8), or pCrl3328
(lanes 3, 6, 9) and labeled with [35S].
Lysates (lanes 1-6) or supernatants
(lanes 7-9) were subjected to immunoprecipitation with
anti-rp5 (lanes 1-3) or with CR-50 antibody
(lanes 4-9). The anti-rp5 antibody, directed against the C terminus of Reelin, recognized the full-length product of pCrl,
but not the truncated product of pCrl3328. CR-50 immunoprecipitated both proteins from the cell lysate, but it only precipitated the full-length protein from the cell supernatant. The migration of a 220 kDa molecular weight marker is indicated.
[View Larger Version of this Image (60K GIF file)]
DISCUSSION
The data presented here demonstrate that Reelin is a
secreted protein that contains the CR-50 epitope. Thus, the
neurodevelopmental defect in reeler mice is a consequence of
the loss of an extracellular signal that is required for the regulation
of neuronal migration. This is clearly the case for the rl
and rltg mice, because no reelin mRNA
is expressed in these strains (D'Arcangelo et al., 1995). However,
reelin mRNA was reported to be present in
rlorl mice. The rlorl
strain has a deletion in the reelin gene that introduces an
out-of-frame deletion in the C terminus (Curran et al., 1995; Hirotsune
et al., 1995). Interestingly, when we introduced a similar mutation into Reelin, the protein was no longer secreted (Fig. 7), indicating that the C-terminal region is essential for maturation and export. Thus, the rlorl strain also may be missing
extracellular Reelin because of a failure in protein transport.
The demonstration that the CR-50 epitope is encompassed within the
reelin coding sequence allows interpretation of the effects of the CR-50 monoclonal antibody in terms of the function of Reelin. CR-50 recognizes an antigen in normal brain that is absent in reeler (Ogawa et al., 1995). The antigen distribution mainly
parallels reelin mRNA expression in the developing cerebral,
cerebellar, and hippocampal cortices. In addition, CR-50 applied
extracellularly recognizes cell types, such as Purkinje cells in the
cerebellum, that do not express reelin mRNA (Miyata et al.,
1996a). This could reflect the interaction of extracellular Reelin with
a receptor located on the surface of Purkinje cells. CR-50 alters the
aggregation pattern of cortical cell cultures in vitro
(Ogawa et al., 1995), the organization of the Purkinje cell plate in
cerebellar explants (Miyata et al., 1996b), and the formation of
hippocampal layering in vivo (Nakajima et al., 1996). These
effects closely resemble the phenotype of reeler mice in
which Reelin is absent. Our demonstration that CR-50 recognizes a
Reelin peptide epitope indicates that the antibody interferes with
Reelin activity directly.
In cerebral, cerebellar, and hippocampal cortices, neuronal cells
located superficially, near the pia, synthesize and secrete Reelin from
the earliest stages of development. Other neuronal cell types, located
in deeper positions, may become responsive to the Reelin extracellular
signal by virtue of the presence of an as yet unidentified cell surface
receptor. These target cells migrate from the ventricular layer toward
more superficial layers along radial fibers. The termination of their
migration, and therefore their ultimate location, is determined by the
Reelin signal. However, the exact outcome of the interaction with
Reelin with its receptor is likely to vary according to the cell
type.
At early stages of mouse cerebral cortex development (embryonic
day 10-12), a preplate composed of Cajal-Retzius and subplate cells
is present. The Cajal-Retzius cells are neurons destined to reach the
most superficial layer (layer I or marginal zone), where they fully
differentiate into horizontal cells (Marin-Padilla and Marin-Padilla,
1982; Derer and Derer, 1990). The subplate neurons are destined to
reside in the deepest layer of the cortical plate (layer VIB; Shatz et
al., 1988). In normal brain, the Cajal-Retzius cells produce and
secrete Reelin into the preplate extracellular environment. The
preplate then splits into two components, the marginal zone and the
subplate layer, and the cortical plate develops between them (embryonic
day 13-16) (Marin-Padilla, 1978). Reelin remains closely associated
with the surface of Cajal-Retzius cell bodies and processes (Ogawa et
al., 1995), some of which may descend into the cortical plate that is
developing underneath (Marin-Padilla, 1978). In the reeler
brain, Cajal-Retzius cells do not produce extracellular Reelin, the
preplate does not split, and the cortical plate develops ectopically
underneath subplate neurons. Because the failure of the preplate to
split is the earliest event associated with the reeler
phenotype (Goffinet, 1979), it is possible that subplate neurons
represent target cells that are repelled by Reelin. This interpretation
is consistent with the observation that dissociated cells from the
reeler cortex are more adhesive than normal, particularly the cells that are born early (embryonic day 10-12; Hoffarth et al.,
1995). The separation of subplate cell bodies from the Cajal-Retzius cell layer may be a consequence of an active repulsion event associated with cell body or dendrite retraction, or it could result from maturation-dependent translocation of subplate cell bodies, a consequence of apical dendrites anchoring to the Reelin-rich marginal zone (Marin-Padilla, 1988). Alternatively, Reelin might preferentially attract cortical plate neurons to migrate past the subplate toward the
marginal layer. This hypothesis requires either that Reelin must be
able to diffuse into the developing cortical plate or that
Cajal-Retzius processes must come in direct contact with cortical
plate neurons. Given the solubility of Reelin demonstrated in the
present study and the observation that some Cajal-Retzius cell
processes descend into the cortical plate (Marin-Padilla, 1978), this
latter hypothesis is also viable.
In the developing hippocampus, Cajal-Retzius-like cells in the
marginal zone express Reelin (data not shown), which orchestrates the
laminar organization of the hippocampus proper and the dentate gyrus.
These cells, like the neocortical Cajal-Retzius cells, are generated
very early during development and occupy a superficial layer (Soriano
et al., 1994). However, a more detailed analysis of the early cell
interactions involved in hippocampus formation is required to formulate
a hypothesis on the mode of action of Reelin in this as well as other
structures affected by the reeler mutation.
In the embryonic cerebellum, Reelin is produced by neuronal precursors
in the nuclear transitory zone that are destined to give rise to cells
of the deep nuclei and by postmitotic neurons in the deepest part of
the external granular layer and in the internal granular layer
(D'Arcangelo et al., 1995; Ogawa et al., 1995; Miyata et al., 1996a).
No expression was detected in Bergmann glia or in Purkinje cells. In
the normal cerebellum, Purkinje cells form a plate underneath the
external granule layer, and they develop complex dendritic trees in the
molecular layer. Reelin-positive postmitotic granule neurons migrate
inwardly, crossing the molecular layer and the Purkinje cell body layer
to form the internal granule layer, where they lose Reelin
extracellular immunoreactivity (Miyata et al., 1996a). In
reeler mice, Purkinje cells do not form a cortical plate,
but they remain ectopically located in the deep cerebellar nuclear
mass. Because Purkinje cells accumulate Reelin on the extracellular
membrane (Miyata et al., 1996a), it is conceivable that they express a
receptor that mediates an increased adhesion with Reelin-producing
granule cells. Recent functional studies demonstrate that the CR-50
antibody interferes with the formation of the Purkinje cell layer
(Miyata et al., 1996b). Thus, it is conceivable that a common
Reelin-dependent mechanism underlies the formation of both the cortical
plate in the cerebral cortex and the Purkinje cell layer in the
cerebellar cortex.
A general consideration from all the reported studies is that Reelin is
expressed by specific neuronal populations to help other neurons
determine their correct positioning in developing laminar structures.
So far, Reelin expression or binding activity has not been described in
radial fibers despite the fact that the orientation and the end feet of
radial fibers are abnormal in the reeler brain (Derer,
1979). Recent findings suggest that Cajal-Retzius cells produce a
factor that affects radial fiber development (E. Soriano, personal
communication). Thus, it is possible that Reelin may affect the
formation of the radial glia scaffold indirectly. It is to be hoped
that some of the questions concerning the development of laminar
organization in brain structures will be resolved by the identification
and characterization of proteins that interact with Reelin, including
potential cell surface receptors and possibly other extracellular
signaling molecules.
FOOTNOTES
Received Sept. 5, 1996; revised Oct. 3, 1996; accepted Oct. 4, 1996.
This work was supported in part by National Institutes of Health Cancer
Center Support CORE Grant P30CA21765, the American Lebanese Syrian
Associated Charities, National Research Service Award NSO9698 from
National Institute of Neurological Disorders and Stroke (G.D.), the
Science and Technology Agency of the Japanese Government, and the
Ministry of Education, Science, and Culture of Japan. We thank M. Sheldon, D. Eberhart, R. Homayouni, and J. Morgan for critically
reading this manuscript and the members of the animal facilities of St.
Jude Children's Research Hospital and the Institute of Physical and
Chemical Research for their help to maintain animals.
Correspondence should be addressed to Dr. Tom Curran, Department of
Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
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PNAS,
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97(17):
9729 - 9734.
[Abstract]
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Y. Jossin and A. M. Goffinet
Reelin Does Not Directly Influence Axonal Growth
J. Neurosci.,
December 1, 2001;
21(23):
RC183 - RC183.
[Abstract]
[Full Text]
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