1 UNC Neuroscience Center and the Department of Cell and Molecular Physiology,
The University of North Carolina School of Medicine, Chapel Hill, NC 27599,
USA
2 Department of Biological Sciences, Stanford University, Stanford, CA 94305,
USA
3 Department of Medicine, Children's Hospital, Boston and Department of
Pediatrics, Harvard Medical School, Boston, MA 02115, USA
* Author for correspondence (e-mail: anton{at}med.unc.edu)
Accepted 29 September 2004
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SUMMARY |
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Key words: Cerebral cortex, Migration, Adhesion
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Introduction |
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We have tested this hypothesis using real-time analysis of neuronal
migration in wild type and 3ß1 integrin-deficient embryonic
cerebral cortex. BrdU birthdating indicates that the preplate splits normally
in the
3 integrin mutant cortex. However, radial and tangentially
directed neuronal migration that follows, proceeds at a significantly slower
rate in the absence of
3ß1 integrin. By contrast, ventricular zone
directed migration is not affected in mutant cortices. Deficits in neuronal
migration are accompanied by the inability of
3ß1
integrin-deficient migrating neurons to display the characteristic probing
extensions and retractions at their leading and trailing edges. Real-time
imaging of actin dynamics in the leading edges of wild-type and
3
integrin/ cortical cells indicates a significant
deficit in the dynamic activity of actin filaments that underlie filopodial
and lamellipodial activity in
3 integrin/
cells. This deficit is rescued by ectopic expression of
3 integrin in
3 mutant cells. Furthermore, intercross between
3 integrin
mutant mice and a Thy1-GFP transgenic mouse line expressing GFP specifically
in layer 6 (Feng et al., 2000
)
indicates misplacement of neurons normally destined for layer 6 in
3
integrin mutant cortices. Similar displacement is also evident in calbindin or
calretinin positive upper layer neurons. The inability to migrate normally and
deficits in the ability to engage cues such as fibronectin or reelin, which
are present along the migratory route, may underlie the misplacement of
neurons in the cerebral cortex of
3 integrin mutant mice.
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Materials and methods |
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BrdU birthdating studies
Pregnant mice were injected intraperitoneally with BrdU (7.5 mg/kg body
weight, dissolved in saline; Boehringer-Mannheim) on embryonic days 10.5 or
11.5. At E16.5, brains were removed, fixed in 70% ethanol, embedded in
paraffin wax, cut into cut into 10 µm thick coronal sections, and processed
for BrdU labeling as described earlier
(Anton et al., 1996).
Comparison between sections from different embryos were obtained from
identical cortical regions corresponding approximately to posterior frontal,
parietal and anterior occipital areas.
Preparation of embryonic cortical slices for time-lapse imaging
Coronal slices (150 µm) of embryonic day 15 wild-type and littermate
3 integrin mutant cortices were incubated with 12.5 µm Oregon Green
488 BAPTA-1 AM (Molecular Probes #O-6807) diluted in neurobasal medium at
37°C for 1 hour. Slices were then washed three times in DMEM/10% FBS
medium and cultured on gel matrix (1 mg/ml)-coated glass bottom microwell
petri dishes (MatTek) overnight. Labeled neurons in the intermediate zone of
medial cerebral wall from regions approximately corresponding to parietal,
occipital cortical areas were then imaged repeatedly every 10-25 minutes for
2-3 hours using a Zeiss Pascal inverted laser-scanning microscope equipped
with live tissue incubation chamber (see Fig. S2A in the supplementary
material). The rate of migration of the monitored cells was measured using
LSM5 Pascal program (Zeiss). To label tangentially migrating neurons from the
ganglionic eminence, 0.5 µl of Oregon Green 488 BAPTA-1 AM (250 µM) was
applied to ganglionic eminence of cortical slices with a pulled glass
micropipette (see Fig. S2B in the supplementary material). Slices were then
processed and imaged as described earlier. In some experiments, slices were
infected with adenoviral vectors expressing GFP (3.125x108
vector genomes/ml media; gift from Dr K. Fisher, Tulane University) for 1 day
before imaging of labeled neurons. The number of all protrusions and
retractions in the leading and trailing edges of GFP labeled cells were
counted. Activity index indicates number of extensions or
retractions/hour.
Electroporation of cortical cells
E14 cortices from wild-type and 3 null embryos were briefly
dissociated into small aggregates in ice-cold DMEM+10% FBS, electroporated
with 3 µg of pEGFP-actin (BD Biosciences),
3 integrin (gift of Dr
Kreidberg, Harvard Medical School), PH domain from Akt-EGFP or Rac-EGFP
plasmid DNA (gift of Dr Snider, UNC) using the Mouse Neuron Nucleofector kit
(Amaxa, Cologne, Germany) as per the manufacturer's instructions. The
electroporated tissue aggregates were then dissociated and plated in DMEM+10%
FBS on glass bottom microwell dishes coated with poly-D-lysine (0.5 mg/ml) and
ECM gel matrix (2 mg/ml; Sigma-Aldrich). After 24-48 hours in vitro, time
lapse images of transfected cells were recorded for 15 minutes at 30 second
intervals using a Zeiss Pascal inverted laser-scanning microscope equipped
with a live tissue incubation chamber.
3 integrin expression in the
rescue experiments was confirmed by immunolabeling of rescued cells (GFP
positive) with anti-
3 integrin antibodies (Becton-Dickinson).
Analysis of actin microspikes and PH-Akt EGFP labeled leading edge protrusions
The leading edges of EGFP-actin expressing cells were overlaid with a 1000
µm2 box. Individual microspikes inside this area were identified
and the changes in their net length were measured. The percentage actin
microspikes that underwent dynamic changes were also measured. In PH-Akt EGFP
transfected cells, leading edges were overlaid with a 1000 µm2
box and the number of active protrusions in this area was counted.
Antibodies
Cortical interneurons were immunostained with polyclonal anti-Calretinin
(Chemicon Ab5054) or Calbindin (Chemicon Ab1778) antibodies. 3 integrin
antibodies were obtained from BD Transduction Labs (#611045), Chemicon
(AB1920), or generously provided by Dr DiPersio, Albany Medical College (Ab
#8-4).
Embryonic cortical neuron adhesion assay
To measure changes in the response of wild type and 3 integrin
mutant cortical neurons to different, biologically relevant ECM substrates in
vitro, we modified an assay described by Hordivala-Dilke et al.
(Hordivala-Dilke et al., 1998). Briefly, 24-well plates were coated first with
poly-lysine overnight, followed by fibronectin or laminin (10 µg/ml) for 1
hour. Plates were then blocked with bovine serum albumin (10 mg/ml) for 1
hour. E16 cortical cells were suspended in serum-free DMEM and plated out at
50,000 cells per well. After incubation for 1 hour at 37°C, non-adherent
cells were washed off with HBBS and adherent cells fixed with 4%
paraformaldehyde. Adhered neurons were visualized with Tuj1 antibodies. Number
of neurons in 10 sample, 0.2 mm2 fields were counted in each well.
Data shown were based on four independent experiments.
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Results |
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Discussion |
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3ß1 integrin function during neuronal motility
Earlier studies indicated that 3ß1 integrins could modulate
neuron-glial recognition cues during neuronal migration and placement in
cortex (Anton et al., 1999
;
Dulabon et al., 2000
;
Sanada et al., 2004
).
Real-time monitoring of migrating neurons in the embryonic cerebral cortex
provides, at a mechanistic level, information about how signals that are
transduced by
3ß1 integrin affect neuronal migration in the
developing cerebral cortex. Radially and tangentially directed neuronal
migration is affected, with accompanying deficits in actin dynamics and
protrusive edge activity of motile neurons.
3 integrin can influence
oriented neuronal movement in multiple ways. For example,
3 integrins
can influence neuronal response to cues such as fibronectin
(Hodivala-Dilke et al., 1998
),
which is present along the radial glial migratory routes in cerebral cortex
(Pearlman and Sheppard, 1996
;
Sheppard et al., 1991
;
Sheppard et al., 1995
;
Stettler and Galileo, 2004
).
Consistent with this possibility is the observation that
3 integrin
mutant embryonic cortical neurons display enhanced (+62±0.06%) adhesion
to fibronectin substrate in vitro (see Fig. S4 in the supplementary material).
Increased adhesion to ECM cues present along the radial glial migratory guides
may thus play a role in reducing the rate of migration of
3 integrin
mutant neurons. Whether deficits in radial neuronal migration can indirectly
affect the tangential migration of neurons in
3 integrin mutant cortex
remains unclear. However, recent studies indicate that netrin 1, a diffusible
guidance protein, can bind to
3ß1 integrin and regulate hepatocyte
growth factor (HGF) induced haptotaxis of epithelial cells on netrin 1
(Yebra et al., 2003
). HGF is a
motogen for tangentially migrating neurons
(Powell et al., 2001
) and thus
it is conceivable that netrin-
3ß1 interactions may similarly
regulate HGF activity during tangential neuronal migration in embryonic
cerebral cortex.
In keratinocytes, 3ß1 integrin has been shown to promote cell
spreading on laminin 5 and actin fiber assembly and organization
(DeMali et al., 2003
;
Hodivala-Dilke, 1998
).
Integrin
3ß1-deficient keratinocytes also fail to polarize and
engage in oriented migration (Choma et
al., 2004
). Furthermore, cell polarity during oriented cell
migration involves the accumulation of PIP3 in the leading edges of the cells
(Funamato et al., 2002; Wang et al.,
2002
; Weiner et al.,
2002
). Lack of PIP3 dynamics at the leading edge as indicated by
the PH domain of Akt-GFP fusion probe in
3 integrin mutant cells also
suggests a role for
3ß1 integrin in maintaining polarity during
oriented neuronal migration.
Disruption in pial or vascular ECM assembly
(Blackshear et al., 1997;
Graus-Porta et al., 2001
;
McCarty et al., 2002
;
Moore et al., 2002
) or
deficits in ECM components perlecan
(Costell et al., 1999
),
laminin
5 chain (Miner
et al., 1998
) or laminin
1 nidogen binding site
(Halfter et al., 2002
) has
been shown to disrupt corticogenesis.
3ß1 is required for
MMP9-mediated ECM remodeling and assembly during keratinocyte cell motility.
3ß1 integrin may similarly influence ECM remodeling in the
developing cerebral cortex. It is thus possible that in
3ß1
integrin-deficient cortex, deficits in the ability to bind and respond to
ligands in the environment, to remodel ECM or maintain cell polarity may
contribute to retarded neuronal migration.
Intriguingly, migration of neuroblasts towards the ventricular zone occurs
at a normal rate in 3 integrin mutants. These neurons are thought to
originate in the ganglionic eminence and migrate towards ventricular zone to
obtain positional information, prior to radial migration towards the cortical
plate (Nadarajah et al.,
2002
). Lack of significant
3ß1 integrin effect in this
mode of migration is indicative of the specific role integrin mediated
cell-cell adhesion can play in regulating distinct patterns of migration in
the developing nervous system. The behavioral response of a cell to the ECM is
an integrated response determined by the specific components of the ECM
present, and the subset of integrins expressed by that cell. Thus it will be
instructive to determine the repertoire of integrins expressed in neurons
migrating in distinctly different orientations during the development of
cortex.
3 integrin-actin interactions
An important outcome of integrin-ECM engagement induced cytoplasmic
signaling is the promotion of actin assembly
(DeMali and Burridge, 2003;
DeMali et al., 2003
). In
regions of cells where integrins first engage their ligands, such as the
leading edges, a high degree of integrin dependent actin polymerization
activity is evident. Here, integrins are linked to actin filaments by
actin-binding proteins, such as talin, filamin and
-actinin. Members of
the Mena/VASP family are also important regulators of actin filament assembly
at the leading edges, where they are thought to indirectly interact with
integrins to target actin polymerization to new integrin-ECM contact sites
(Calderwood et al., 2000
).
Thus, deficiency of
3 integrin at the leading edge of migrating neurons
may drastically affect the ability of the cell to polymerize actin and,
consequently, impair local reorganization of the actin network needed for
dynamic protrusions at the leading edges. Recent studies also suggest that
changes in the activation of integrin-actin linking protein, such as talin or
actin dynamics itself, could influence integrin function in an inside-out
manner (Bennet et al., 1999; Calderwood et
al., 2000
; Cram and
Schwarzbauer, 2004
; Hynes,
2002
; Kim et al.,
2003
). How such mechanisms are affected in the
3
integrin-deficient cortical neurons remains to be elucidated.
3ß1 integrin function during neuronal placement and cortical layer formation
ß1 integrin in the cerebral cortex can dimerize with at least 10
different subunits, including
3. To date, no other ß
integrin subunit has been shown to associate with
3 integrin subunits.
3ß1 integrin also can associate with itself and with members of
the tetraspanin family of transmembrane proteins, and may transdominantly
inhibit other integrins (Sriramarao et
al., 1993
; Symington et al.,
1993
; Hynes, 2002
;
Hodivala-Dilke et al., 1998
).
Cortical layer formation is disrupted following cre-lox-mediated inactivation
of ß1 integrins in cortical neurons and glia from around embryonic day
10.5 (Graus-Porta et al.,
2001
; Forster et al.,
2002
). Defective meningeal basement membrane assembly,
marginal-zone formation and glial end feet anchoring at the top of the cortex
are thought to lead to this phenotype. Whether the lack of pial anchoring of
radial glial cells in ß1-deficient cortex affect their ability to
function as neuronal stem cells or as neuronal migratory guides, and thus
contribute to the defective placement of neurons in the cortex is unclear. The
varied, non-overlapping cortical phenotypes of ß1,
1,
3,
6 and
v-null mice may reflect the transdominant, transnegative
or compensatory influences distinct integrin receptor dimers may exert over
each other and the ECM ligands in the developing cerebral cortex
(Bader et al., 1998
;
Fassler and Meyer, 1995
;
Gardner et al., 1999
;
Georges-Labouesse et al.,
1998
). For example, in vitro binding of a ligand to a signal
transducing integrin or inactivation of specific integrin subunits can
initiate a unidirectional signaling cascade affecting the function of the
target integrin in the same cell (Blystone
et al., 1999
; Hodivala-Dilke
et al., 1998
; Simon et al.,
1997
). Elucidating how such integrin crosstalk regulates patterns
of neuronal migration in the developing cortex will be crucial to fully
understand the specific role of distinct integrins in corticogenesis.
Pathways of migration and cell-cell interactions during migration crucially
influence layer formation and phenotypic specification of different classes of
cerebral cortical neurons (Anderson et al.,
1997; Parnavelas,
2000
; Sanada et al.,
2004
). The changing patterns of adhesive interactions mediated by
integrins during neuronal translocation across the cerebral wall may not only
control the trajectory of neurons, but may also trigger the developmental
programs needed for progressive acquisition of distinct cortical neuronal
phenotypes. Evaluation of whether the neurons that have undergone altered
patterns of migration and placement in the absence of
3 integrin
subunit develop the full complement of layer-specific characteristics of
distinct cortical neurons awaits the generation of cell-type specific or
inducible
3 integrin mutant mouse models. However, the results shown
here demonstrate the significance of
3 integrin-mediated signaling in
distinct patterns of neuronal migration and the eventual positioning of
neurons in specific layers of the developing cortex.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/131/24/6023/DC1
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