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The Journal of Neuroscience, November 15, 1998, 18(22):9365-9375
Heterotopic Neurogenesis in a Rat with Cortical Heterotopia
Kevin S.
Lee,
Jennifer L.
Collins,
Matthew J.
Anzivino,
Eric A.
Frankel, and
Frank
Schottler
Departments of Neuroscience and Neurological Surgery, University of
Virginia, Charlottesville, Virginia 22908
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ABSTRACT |
Early cellular development was studied in the neocortex of the
tish rat. This neurological mutant is seizure-prone and displays cortical heterotopia similar to those observed in certain epileptic patients. The present study demonstrates that a single cortical preplate is formed in a typical superficial position of the developing tish neocortex. In contrast, two cortical plates are formed: one in a
normotopic position and a second in a heterotopic position in the
intermediate zone. As the normotopic cortical plate is formed, it
characteristically separates the subplate cells from the superficial
Cajal-Retzius cells. In contrast, the heterotopic cortical plate is not
intercalated between the preplate cells because of its deeper position
in the developing cortex. Cellular proliferation occurs in two zones of
the developing tish cortex. One proliferative zone is located in a
typical position in the ventricular/subventricular zone. A second
proliferative zone is located in a heterotopic position in the
superficial intermediate zone, i.e., between the two cortical plates.
This misplaced proliferative zone may contribute cells to both the
normotopic and heterotopic cortical plates. Taken together, these
findings indicate that misplaced cortical plate cells, but not preplate
cells, comprise the heterotopia of the tish cortex. Heterotopic
neurogenesis is an early developmental event that is initiated before
the migration of most cortical plate cells. It is concluded that
misplaced cellular proliferation, in addition to disturbed neuronal
migration, can play a key role in the formation of large cortical heterotopia.
Key words:
heterotopia; neurogenesis; cortical development; epilepsy; preplate; tish rat
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INTRODUCTION |
Malformations of the human neocortex
are present in >1% of the general population and in ~20-40% of
intractable epileptics (Meencke and Janz, 1984 ; Hardiman et al., 1988;
Farrell et al., 1992; Meencke and Veith, 1992; Mischel et al., 1995).
These malformations range in severity from minor displacements of a few
neurons to massive rearrangements of cortical structure. Traditionally,
clinical classification systems have lumped most of these malformations into the category of "neuronal migration disorders" (e.g., Palmini et al., 1993). However, it has become increasingly evident that disturbances in other developmental events, such as cellular
proliferation and programmed cell death, also contribute to cortical
malformations (Rakic, 1988; Evrard et al., 1989; Barkovich et al.,
1992, 1996; Rorke, 1994; Eksioglu et al., 1996; Kuida et al., 1996;
Brunstrom et al., 1997).
One of the most profound types of human cortical malformation is
subcortical band heterotopia (SBH), or double cortex. Subcortical band
heterotopia are characterized by a large collection of heterotopic neurons located below the normotopic neocortex (Matell, 1893; Jacob,
1936; Barkovich et al., 1989). Individuals affected with this disorder
are subject to intractable epilepsy and mental retardation (Barkovich
et al., 1989; Livingston and Aicardi, 1990; Vahldiek et al., 1990;
Palmini et al., 1991; Ricci et al., 1992; Soucek et al., 1992;
Hashimoto et al., 1993; Iannetti et al., 1993; Battaglia et al., 1994).
The developmental mechanisms responsible for many human cortical
malformations, including band heterotopia, remain largely unknown.
Moreover, the paucity of appropriate animal models of human cortical
malformations makes it difficult to examine such issues experimentally.
Recently, a seizure-prone mutant rat (tish) was discovered that
displays inherited band heterotopia similar to those of the human
malformation of SBH (Lee et al., 1997). The heterotopic cells in tish
display various features that are characteristic of neocortical cells,
including cellular morphology, afferent connectivity, efferent
connectivity, and contemporaneous neurogenesis with the neocortex (Lee
et al., 1997; Schottler et al., 1998). The tish rat thus
represents a genetic animal model for (1) characterizing the
developmental mechanisms involved in the formation of a human-like
cortical malformation and (2) evaluating the roles of heterotopic
neurons in the genesis and maintenance of epilepsy.
To identify potential mechanisms participating in the formation
of cortical heterotopia, a series of experiments was undertaken to
examine the distribution of Cajal-Retzius and subplate cells. These
cells comprise the preplate during early cortical development (Marin-Padilla, 1978) and are believed to influence cortical
organization through effects on cellular lamination (D'Arcangelo et
al., 1995; Ogawa et al., 1995) and afferent/efferent connectivity
(McConnell et al., 1989; Ghosh et al., 1990; DeCarlos and O'Leary,
1992; Ghosh and Shatz, 1992, 1993; Allendoerfer and Shatz, 1994).
Disturbances in these cells could have severe consequences for proper
cortical development. A second series of experiments examined cellular proliferation and migration in the developing tish cortex. Although band heterotopia are generally regarded as neuronal migration disorders, alterations in cellular proliferation could also contribute to the misplacement of neurons.
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MATERIALS AND METHODS |
Breeding. All procedures were approved by the
University of Virginia Animal Research Committee. Female animals were
placed in the home cage of a male animal at 5 P.M. and removed the
following morning at 9 A.M. The tish phenotype is inherited in an
autosomal recessive pattern (Lee et al., 1997), but this phenotype
cannot be recognized easily by visual inspection of the brain until
approximately embryonic day 17 (E17). Consequently, experiments in
which animals were killed before E18 involved the pairing of (1) two
homozygous tish animals to ensure all homozygous (tish/tish)
affected offspring or (2) a tish animal and a wild-type (+/+) animal to
ensure all heterozygous (tish/+) unaffected offspring.
Homozygous breeders were identified by either magnetic resonance
imaging of the brain to verify the tish phenotype (Lee et al., 1997) or
by histological verification of the tish phenotype in both parents of
both of the breeders. In experiments in which animals were killed at
later stages of development, one homozygous affected animal was paired with a heterozygous unaffected animal, producing a mix of ~1:1 affected and unaffected offspring. Heterozygous animals, which exhibit
a normal phenotype, were used as controls in all experiments. Vaginal
smears were taken the morning after the pairing, and sperm-positive females were placed in maternity cages and given food and water ad libitum. The day on which a sperm-positive smear was
identified was defined as E1. The day of birth was defined as postnatal
day 1 (P1).
Bromodeoxyuridine labeling. Pregnant dams were
injected intraperitoneally on either E15 or E18 with
5-bromo-2'-deoxyuridine (BrdU) [50 µg/g body weight, in 0.007N NaOH
with 0.9% NaCl (Sigma, St. Louis, MO)]. Dams were anesthetized with
ketamine/xylazine (66:7 mg/kg) at 2 hr or 24 hr after BrdU injection,
and pups were removed by hysterotomy. Pups were decapitated, and their
heads were fixed by immersion in 70% ethanol overnight. The brains
were removed, dehydrated in graded ethanols, cleared in xylenes, and embedded in paraffin. The brains were sectioned coronally at a thickness of 6 µm with a microtome, and sections were mounted on
microscope slides. The sections were deparaffinized, rehydrated, and
processed for BrdU immunohistochemistry using the avidin-biotin complex (ABC) technique as described in detail by Takahashi et al.
(1992). Briefly, sections were immersed in 2N HCl for 30 min, neutralized in PBS for 3 min, and then incubated with primary antibody [anti-BrdU, mouse monoclonal (Becton Dickinson, Cockeysville, MD)] at a dilution of 1:100 in PBS with 0.5% Tween 20 for 60 min. Sections were rinsed in PBS and incubated in biotinylated secondary antibody [Elite anti-mouse IgG kit, 1:200 (Vector Laboratories, Burlingame, CA)] for 30 min. The sections were then processed with ABC
(Vector) for 30 min, rinsed in PBS, and visualized with VIP (Vector) or
DAB (Sigma). Sections were dehydrated in graded ethanols, cleared in
xylenes, and coverslipped using Permount.
In another set of experiments, pregnant dams were injected with BrdU on
late E13 or early E14. On P1, the offspring were anesthetized by
hypothermia and decapitated, and the brains were immersed in 4%
paraformaldehyde in 0.1 M phosphate buffer, pH 7.4. The
brains were then sectioned and prepared for BrdU histochemistry as
described above, except that the sections were treated with trypsin
(0.1% in 0.1 M Tris buffer, pH 7.5, with 0.1%
CaCl2) after rehydration.
Calretinin immunohistochemistry. Calretinin-positive neurons
were identified in the developing tish and control cortices at E15,
E18, and E20. Dams were anesthetized, and the brains of pups were fixed
in ethanol, embedded in paraffin, and sectioned coronally as described
in the preceding paragraphs. The sections were deparaffinized in
xylenes, rehydrated through a series of graded ethanols, and rinsed in
distilled water. Incubation with primary antibody [anti-calretinin; rabbit polyclonal (Chemicon, Temecula, CA)] was performed at a dilution of 1:500 for 60 min in the presence of 1% goat serum and
0.5% Tween 20. Sections were rinsed in PBS and incubated in biotinylated secondary antibody (Elite anti-rabbit IgG kit, 1:200; Vector) for 30 min. The sections were then treated with ABC (Vector) for 30 min, rinsed in PBS, and visualized using VIP (Vector) for 5 min.
Sections were counterstained with methyl green. Sections were
dehydrated in graded ethanols, cleared in xylenes, and coverslipped using Permount.
CR-50 immunohistochemistry. Dams were
anesthetized and E20 pups were removed by hysterotomy. The pups were
perfused intracardially with heparinized saline and then a fixative of
4% paraformaldehyde in phosphate buffer. The heads were placed in the
fixative solution overnight at 4°C. The brains were removed and
placed in 25% sucrose in PBS until they sank. The brains were then
frozen rapidly and sectioned coronally at a thickness of 20 µm with a
cryostat. The sections were placed on microscope slides and processed
for CR-50 immunoreactivity in a manner similar to that described
by Ogawa et al. (1995). Briefly, sections were preincubated in a
blocking solution of 10% horse serum for 30 min. Incubation with
primary antibody (CR-50, mouse monoclonal) was performed at a dilution of 1:500 in blocking solution for 60 min. The CR-50 antibody was provided by Dr. Masaharu Ogawa (Kochi Medical School). Sections were
rinsed in PBS and incubated in biotinylated secondary antibody (Elite
anti-mouse IgG kit, 1:200; Vector) for 30 min. The sections were then
treated with ABC (Vector) for 30 min, rinsed in PBS, and visualized
using VIP (Vector) for 30 sec. Sections were dehydrated and cleared in
graded ethanols and xylenes and then coverslipped using Permount.
Proliferating cell nuclear antigen immunohistochemistry.
Proliferating cell nuclear antigen (PCNA)-positive neurons were
identified in the developing neocortices of tish and control embryos at
E15 and E18. Pregnant dams were anesthetized with ketamine/xylazine (66:7 mg/kg), and pups were removed by hysterotomy. Pups were decapitated, and their heads were fixed overnight by immersion in 70%
ethanol. The brains were removed, dehydrated through graded ethanols,
cleared in xylenes, and paraffin-embedded. Coronal sections were cut at
a thickness of 6 µm with a microtome and slide-mounted. Tissue
sections were then deparaffinized in xylenes and rehydrated through
graded ethanols and treated with 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, for 30 min at room temperature. Slides were rinsed and placed in Coplin jars with 1× saline sodium citrate buffer (SSC), pH 6.0, brought to a boil in a microwave oven,
and allowed to cool to room temperature. Tissue was neutralized by two
rinses in phosphate buffered saline (PBS). The sections were blocked
and permeabilized with PBS, pH 7.4, containing 10% horse serum/0.25%
Triton X-100 for 30 min. Incubation with primary antibody (anti-PCNA,
mouse monoclonal; Novocastra, Newcastle upon Tyne, UK) was performed at
a dilution of 1:200 in the above medium for 60 min. Sections were
rinsed in PBS and incubated in biotinylated secondary antibody (Elite
anti-mouse IgG kit, 1:200; Vector) for 30 min. After a PBS rinse, the
sections were processed with ABC (Vector) for 30 min, rinsed in PBS
again, and visualized with VIP (Vector). Tissue sections were then
dehydrated through graded ethanols, cleared in xylenes, and
coverslipped using Permount.
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RESULTS |
Development of the cortical preplate
The distribution of the calcium-binding protein calretinin was
examined in the neocortex of tish and control animals on E15, E18, and
E20. Previous work has shown that anti-calretinin antibodies label both
Cajal-Retzius cells and subplate cells during early cortical
development (Fonseca et al., 1995). At later stages of cortical
development (i.e., when subplate cells become separated from the
Cajal-Retzius cells by the developing cortical plate), calretinin
labeling is most prominent in the subplate, whereas progressively fewer
cells are labeled in the marginal zone (Fonseca et al., 1995). In the
present study, large- and medium-sized calretinin-positive cells are
located in the superficial aspect of the E15 control cortex (Fig.
1). The placement and sizes of these
cells correspond to those of cortical preplate cells. In E18 control
animals, calretinin-positive cells are most prominent at the base of
the developing cortical plate, and some labeled cells are present in
the developing cortical plate and marginal zone (Fig. 1). By E20, most
of the cell labeling is found in the subplate, with a few cells
scattered in the cortical plate and marginal zone (Fig. 1). These
findings in control animals are consistent with previous observations
of calretinin immunoreactivity in the developing rat cortex (Fonseca et
al., 1995).
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Figure 1.
Calretinin-positive neurons in the developing
cortex. Anti-calretinin immunohistochemistry is shown for control and
tish animals at E15, E18, and E20. In each frame, the pial surface is
toward the top of the micrograph, and the ventricle is
toward the bottom. Calretinin-positive cells
(dark purple) are present in the cortical preplate at
E15 in both control and tish animals. At E18 and E20, cell staining is
most prominent in the subplate at the base of the normotopic cortical
plate in both control and tish animals. A few stained cells are present
in the marginal zone and the overlying cortical plate in both animals.
The arrows in tish E20 indicate the
heterotopic cortical plate, and the asterisks indicate
the normotopic cortical plate. Scale bars: E15, 50 µm;
E18, 100 µm; E20, 200 µm.
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The developing tish cortex exhibits a pattern of calretinin
immunoreactivity that is generally similar to that of control animals.
At E15, cell labeling is concentrated in a superficial position in the
developing tish cortex (Fig. 1). By E18, the architectonic organization
of the developing tish cortex can be differentiated from that of
control animals by the presence of two cortical plates (Fig.
2). One cortical plate is located in a
normotopic position between the marginal zone and the subplate (Figs.
1, 2); this normotopic cortical plate is thinner than that of control
animals. A second, heterotopic cortical plate (Figs. 1, 2) is located
below the subplate in the intermediate zone. The subventricular and ventricular zones appear thinner in the tish rat than in controls (Fig.
2). Calretinin-positive cells are most prominent in the subplate at E18
and E20, with a few scattered cells in the overlying cortical plate and
marginal zone (Fig. 1). There are few, if any, calretinin-positive
cells in the developing heterotopic cortical plate (Fig. 1). These
findings indicate that subplate neurons are restricted to a normal
position at the base of the normotopic cortical plate in tish
animals.
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Figure 2.
Cytoarchitecture and heterotopic mitotic profiles
in the developing tish cortex. Nissl-stained sections are shown from
control and tish animals at E18. The
top frames are cresyl violet-stained paraffin sections
that extend from the pial to the ventricular surfaces. The cortical
plate (CP), ventricular zone (VZ), and
subventricular zone (SVZ) are thinner in the developing
tish cortex than in the developing control cortex. Two unique features
of the tish cortex are a heterotopic cortical plate
(CPH) and a heterotopic zone of mitotic profiles.
The CPH is located in the middle of the area that is normally the
intermediate zone (IZ) in control animals. Heterotopic
mitotic profiles are located between the CPH and the overlying
normotopic cortical plate (CPN) and are
positioned in the area that is normally the superficial aspect of the
intermediate zone in control animals. The bottom frames
show higher-magnification photomicrographs of thionin-stained semithin
sections of the tish and control cortices at E18. The photomicrographs
cover the superficial aspect of the developing cortex, including the
marginal zone (MZ), cortical plate, and superficial
intermediate zone. The marginal zone is relatively cell-sparse, whereas
the developing cortical plate contains densely packed neurons in both
animals. The superficial intermediate zone of the tish animal contains more cell
bodies than the corresponding area of the control animal. In addition,
the superficial intermediate zone of tish animals contains mitotic
profiles (arrowheads) that exhibit both symmetric and
asymmetric cleavage planes. These profiles are indicative of ongoing
mitosis in the superficial intermediate zone of the tish cortex. In
contrast, mitotic profiles are relatively rare in the superficial
intermediate zone of control animals. Scale bar: top
frames, 90 µm; bottom frames, 40 µm.
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Cajal-Retzius cells produce an extracellular matrix protein (reelin)
that is thought to form part of a signaling cascade regulating cortical
lamination. A failure in the expression of reelin in Cajal-Retzius
cells of the reeler mutant mouse (D'Arcangelo et al., 1995; Ogawa et
al., 1995) is associated with improper cortical lamination in which
later-generated neurons are incapable of migrating past
earlier-generated neurons (Caviness et al., 1988). Ogawa and associates
(1995) have developed a monoclonal antibody (CR-50) that recognizes
reelin, and immunohistochemical studies demonstrate that this antibody
can be used to selectively label Cajal-Retzius cells. In the present
experiments, CR-50 immunohistochemistry was used to determine the
location of Cajal-Retzius cells in the tish cortex of E20 animals. In
control animals, a band of immunoreactivity is present in the marginal
zone, with little staining in other layers of the cortex (Fig.
3). This pattern of staining is
consistent with previous observations in which CR-50 selectively
labeled Cajal-Retzius cells in the marginal zone of the mouse cortex
(Ogawa et al., 1995). A similar pattern of staining is observed in the marginal zone of tish animals, with little staining in other portions of the normotopic or heterotopic cortices (Fig. 3). These findings suggest that Cajal-Retzius cells are restricted to a normotopic position in the marginal zone of the developing tish cortex.
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Figure 3.
Distribution of reelin in the developing cortex.
CR-50 immunohistochemistry is shown for control and
tish animals at E20. A band of immunoreactivity is
observed in the marginal zone (arrow) of control
animals, with little staining seen in other layers of the cortex. A
similar band of immunoreactivity is present in the marginal zone
(arrow) of tish animals, with little staining in other
portions of the normotopic or heterotopic cortices. These sections are
not counterstained, and V indicates the position of the
ventricle. Scale bar, 200 µm.
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It is conceivable that the expression of a particular protein, such as
calretinin or reelin, could be disturbed in a neuron, but that the
neuron could still be present in appropriate and inappropriate
positions. For instance, reelin is not expressed in Cajal-Retzius cells
in the cortex of the reeler mouse, although these neurons are present
in their appropriate position (Ogawa et al., 1995). The possibility
that early-generated preplate neurons are actually present in the
heterotopic cortex, but do not express calretinin or reelin, was
therefore examined. Pregnant rats were injected with BrdU on late E13
or early E14; this time frame corresponds to the
primary period of neurogenesis for Cajal-Retzius and subplate cells in
rats (Valverde et al., 1989; Bayer and Altman, 1990, 1991). Offspring
were killed on P1 to determine the location of BrdU-positive neurons at
a time point when the Cajal-Retzius cells are normally located in the
marginal zone and subplate cells are positioned in the subplate. Darkly
stained, BrdU-positive cells are concentrated in the marginal zone and
subplate of control P1 animals after E13/E14 injections (Fig.
4). A similar pattern of BrdU staining is
observed in the marginal zone and subplate of tish animals (Fig. 4). In
contrast, few if any darkly stained cells are observed in the
heterotopic cortex. These findings reinforce the concept that
early-generated preplate cells are restricted to their normotopic
positions in the tish cortex.
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Figure 4.
Placement of early-generated cells in the
developing cortex. The left frames show BrdU-positive
cells (stained dark black) in the cortices of
control and tish animals that were
labeled in utero with BrdU on late E13 or early E14 and
killed on P1. Darkly labeled cells are concentrated in
the marginal zone and subplate of both control and tish animals. The
heterotopic cortex of the tish animal displays few, if any,
BrdU-labeled cells. The right frames show cresyl
violet-stained sections from the same animals to provide a reference to
the cytoarchitecture. Scale, 200 µm. M, Marginal zone;
CP, cortical plate; SP, subplate;
WM, white matter; CPN, normotopic
cortical plate; CPH, heterotopic cortical plate. Scale
bar, 200 µm.
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Cellular proliferation and initial migration
Cellular proliferation and migration were investigated in the tish
cortex by injecting BrdU into dams on E15 or E18 and killing embryos at early time points after injection. By killing embryos at 2 hr or 24 hr after injection, it is possible to identify the sites of
neuronal proliferation and their initial paths of migration, respectively. Two hours after an injection on E15, BrdU-labeled cells
in the cortex of control rats are concentrated in a band in the
ventricular zone of the developing cortex (Fig.
5; E15-2h); this finding is
consistent with previous studies of neurogenesis in the rat brain
(Bayer and Altman, 1991). In contrast, labeled cells in the E15 tish
brain are found in the superficial aspect of the developing cortex, as
well as in their typical position in the ventricular zone (Fig. 5;
E15-2h). Two hours after an injection on E18, both control
and tish rats exhibit characteristic labeling of cells in the
ventricular and subventricular zones (Fig. 5; E18-2h).
However, in the tish cortex, BrdU-labeled cells are also present in the
intermediate zone. A distinct band of labeled cells is present in the
superficial aspect of the intermediate zone, which is located below the
subplate and above the developing heterotopic cortical plate.
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Figure 5.
Cellular proliferation and initial migration in
the cortex. BrdU-positive cells (stained dark black) are
shown in sections from animals that were labeled in
utero on E15 or E18 with BrdU. The pial surface of the
developing cortex is at the top of each micrograph. Two
hours after an injection of BrdU on E15 (E15-2h),
labeled cells in control animals are found in a restricted band in the
ventricular zone. In the tish rat, BrdU-positive cells are present in
both the ventricular zone and in the more superficial aspect of the
developing cortex at E15-2h. Two hours after an
injection of BrdU on E18 (E18-2h), both
control and tish brains exhibit labeled
cells that are characteristically positioned in the vicinity of the
ventricular zone. In the tish brain, an additional, heterotopic zone of
labeled cells is present in the intermediate zone, with a band of cells
in the superficial intermediate zone (arrows).
Twenty-four hours after an E18 injection of BrdU
(E18-24h), some of the labeled cells have begun to
migrate outward from the normotopic (ventricular) proliferative zone in
both normal and tish brains. In the tish brain, labeled cells also
appear to migrate out of the heterotopic proliferative zone; labeled
cells are found in the deep aspect of the normotopic cortical plate and
in the superficial aspect of the heterotopic cortical plate
(E18-24h). Scale bar: E15-2h, 100 µm;
E18-2h, E18-24h, 200 µm.
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Twenty-four hours after an E18 injection of BrdU, many labeled cells
are moving outward from the normal (ventricular) proliferative zone in
both control and tish animals (Fig. 5; E18-24h). These observations are similar to previous findings in the normal rat brain,
in which labeled cells are found primarily in the subventricular zone
and outer portion of the ventricular zone 24 hr after an injection of
[3H]thymidine on E18 (Bayer and Altman, 1991). In
tish animals, BrdU labeling in the vicinity of the heterotopic
proliferative zone is more dispersed 24 hr after an E18 injection (Fig.
5). Some cells from the heterotopic proliferative zone appear to
migrate into the overlying normotopic cortical plate, whereas others
appear to migrate into the underlying heterotopic cortical plate (Fig. 5; E18-24h). However, the possibility cannot be ruled out
that rapidly migrating cells originating in the normotopic
proliferative zone contribute to these populations of cells. In
addition, the heterotopic proliferative zone is relatively broad at
E18/E19, making it rather difficult to identify unequivocally the
direction of migration of the cells in this area. Longer (i.e., >24
hr) survival times after injection were not examined in detail because the convergence of labeled cells from the two proliferative zones makes
it impossible to distinguish the zone of origin of a given labeled cell.
The preceding findings are consistent with the concept that
heterotopic cellular proliferation occurs in the developing tish cortex. However, an alternative explanation is that a subset of neurons
generated in the normal proliferative zone migrates rapidly into the
superficial intermediate zone (Takahashi et al., 1996). Consequently,
two additional indices of cellular proliferation were examined to
investigate the possibility that heterotopic cellular proliferation
occurs in the developing tish cortex. PCNA is present in mitotically
competent cells, with the highest levels of expression occurring during
S-phase (Morris and Mathews, 1989; Waseem and Lane, 1990; Takahashi and
Caviness, 1993). The distribution of PCNA immunoreactivity was examined
at E15 and E18 in the developing control and tish brains to identify
the sites of cellular proliferation. In E15 control animals,
PCNA-positive cells are located in a typical band in the ventricular
zone of the developing cortex (Fig. 6), similar to the distribution of BrDU-labeled cells at E15-2h
(Fig. 5). In the E15 tish brain, PCNA-positive cells are found in both the ventricular zone and the superficial aspect of the developing cortex. It is unclear whether the heterotopic proliferating cells represent a distinct subpopulation of the progenitor cells; the PCNA-positive cells located in normotopic and heterotopic positions cannot be distinguished from one another on the basis of size or
general appearance in the present material. At E18, PCNA-positive cells
are restricted to the ventricular and subventricular zones of the
control brain (Fig. 6). In contrast, PCNA-positive cells in the tish
brain are located in the ventricular and subventricular zones, and in
the intermediate zone, with a prominent band of cells in the
superficial intermediate zone (Fig. 6). Another index of proliferating
cells is the presence of mitotic profiles. The distribution of mitotic
profiles was investigated in the E18 neocortex by examining semithin
sections stained with thionin. Mitotic profiles in the E18 neocortex
are observed in a characteristic position near the cerebral ventricle
in both control and tish brains. Additional mitotic profiles are
present in the superficial intermediate zone of the tish neocortex but
not the control neocortex (Fig. 2). Taken together, these findings
confirm the presence of heterotopic cellular proliferation in the
developing tish cortex.
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Figure 6.
Distribution of PCNA-positive cells in the
developing cortex. In E15 control animals, PCNA-positive
cells (purple) are located in a typical band in
the ventricular zone. In E18 control animals, labeled
cells are also found at typical sites in the ventricular and
subventricular zones. In E15 tish animals, PCNA-positive cells are
found in both the ventricular zone and in the more superficial aspect
of the developing cortex. In E18 tish animals, labeled cells are
present in the ventricular and subventricular zones, and in a more
superficial (heterotopic) position in the intermediate zone. A
prominent band of PCNA-positive cells is present in the superficial
aspect of the intermediate zone of the developing tish cortex at this
time. Arrows indicate the pial surface of the cortex in
the sections from the E15 animals. Scale bars: E15, 50 µm; E18, 200 µm.
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DISCUSSION |
The widespread use of magnetic resonance imaging in recent
years has revealed a high incidence of cortical malformation in patients with epilepsy and cognitive impairment (Barkovich et al.,
1989, 1992; Palmini et al., 1991; Kuzniecky et al., 1993; Dobyns et
al., 1996; Harding, 1996). Although many human neocortical malformations, including subcortical band heterotopia, are classified as neuronal migration disorders (Barkovich et al., 1989, 1992; Palmini
et al., 1993), the etiologies of these anomalies remain poorly
understood (Barkovich et al., 1996). Our findings indicate that
heterotopic neurogenesis is an early event in the development of a
profound malformation in the rat neocortex. Cortical cells proliferate
in both heterotopic and normotopic proliferative zones in the
developing tish cortex. Cells generated in the heterotopic proliferative zone may migrate into both normotopic and heterotopic cortical plates. These observations indicate that misplaced cellular proliferation, in addition to disturbed neuronal migration, can contribute to the formation of large cortical heterotopia.
Recent evidence indicates that the normotopic and heterotopic cortices
of the tish rat exhibit different patterns of neurogenesis (Lee et al.,
1997). The normotopic cortex displays a typical inside-out neurogenetic
gradient, whereas the heterotopic cortex exhibits a rim-to-core
gradient (Fig. 7). The neuronal
migration disorder hypothesis for the development of this type of
heterotopia (Fig. 7C) predicts that some of the cells
originating in the ventricular proliferative zone arrest their
migration before reaching appropriate destinations; these cells would
then collect to form the heterotopic cortex. The present findings
suggest several alternative hypotheses in which heterotopic
neurogenesis contributes to the formation of cortical heterotopia.
Figure 7D illustrates one variant of the heterotopic
neurogenesis hypothesis in which (1) some cells generated in the
heterotopic proliferative zone migrate outward to form the normotopic
cortex, (2) other cells from the heterotopic proliferative zone migrate
inward to form the superficial aspect of the heterotopic cortex, and
(3) cells from the normal (ventricular) proliferative zone migrate
outward to form the deep aspect of the heterotopic cortex (Fig.
7D). This specific hypothesis also predicts that each of the
three groups of migrating cells constructs a proximal-to-distal
neurogenetic pattern with respect to its initial direction of
migration, i.e., later-formed cells migrate past earlier-born cells in
each case. In this scenario, inside-out neurogenetic gradients are
formed in both the normotopic cortex and deep aspect of the heterotopic
cortex, whereas an outside-in pattern is formed in the superficial
aspect of the heterotopic cortex. This variant of the heterotopic
neurogenesis hypothesis (Fig. 7D) is thus parsimonious with
the observations of the present study and with previous observations
indicating that earlier-generated cortical plate cells (i.e.,
corticothalamic and corticospinal neurons) tend to be concentrated in
the rim area of the heterotopic cortex (Lee et al., 1997).
View larger version (60K):
[in this window]
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|
Figure 7.
Two hypotheses of early cellular
development in the tish cortex. In A, the general
appearance of the adult tish cortex is shown using a Nissl-stained
coronal section of the dorsal cortex. B-D are drawings
of the tish cortex. Neurogenetic gradients in the tish cortex are
illustrated in B. The normotopic cortical plate is
constructed in a typical inside-out manner, with earlier-generated
cells occupying a deeper position than later-generated cells (Lee et
al., 1997). In contrast, the heterotopic cortex develops from its rim
toward its core, with earlier-generated cells located in the peripheral
aspect (rim) of the structure and later-generated cells
located in the central aspect (core) of the structure.
In C and D, the proliferative zones have
been superimposed onto the drawing of the adult cortex to illustrate
their cellular contributions to the developing cortex; this
illustration is not intended to represent ongoing proliferation or the
position of these zones in the adult brain. The traditional
neuronal migration disorder hypothesis
(C) assumes that a subset of neurons derived from
a normal (ventricular) proliferative zone fails to reach the normotopic
cortical plate, creating a secondary, heterotopic cortical plate. In
D, one variant of the heterotopic
neurogenesis hypothesis postulates that a heterotopic
proliferative zone contributes cells to both the normotopic cortical
plate and to the superficial aspect of the heterotopic cortical plate.
In this variant of the heterotopic neurogenesis hypothesis, the
normotopic (ventricular) proliferative zone provides cells to the deep
aspect of the heterotopic cortical plate. It is important to note
that all of the possible combinations of contributions from the two
proliferative zones are not shown in this figure. For instance, the
available data cannot rule out the possibilities that cells from the
ventricular proliferative zone migrate into the normotopic cortical
plate or that cells from the heterotopic proliferative zone migrate
into the deep aspect of the heterotopic cortical plate.
|
|
Clearly, a range of plausible variants of the heterotopic
neurogenesis hypothesis can be constructed in which the two
proliferative zones contribute differentially to the two cortical
plates. To discriminate among these possible variants, it will be
important for future research to identify directly the relative
contributions of the normotopic and heterotopic proliferative zones to
the two cortical plates. Moreover, it will be critical to evaluate
possible disturbances in glial proliferation and function. The thinning of both the ventricular and subventricular zones in the developing tish
cortex suggests that glia, as well as neurons, may be generated in the
heterotopic proliferative zone. Heterotopic proliferation of glial
cells, in particular radial glial cells, could have a profound effect
on cortical development. In the tish rat, it is apparent that many
cortical neurons terminate their migration at inappropriate sites
and/or migrate in the wrong direction during development. Consequently,
any comprehensive hypothesis explaining the development of heterotopia
in the tish cortex will ultimately have to account for errors in both
migration and proliferation.
Cortical preplate cells, unlike cortical plate cells, are not
located heterotopically in the tish cortex. A single preplate is formed
in a normotopic position; subplate cells and Cajal-Retzius cells are
later separated by the development of the normotopic cortical plate.
The absence of a dedicated preplate in the heterotopic cortex could
severely impact the development of heterotopic neurons. For instance,
subplate cells have been shown to play important roles in establishing
appropriate afferent and efferent connectivity of cortical plate cells
(Ghosh et al., 1990; DeCarlos and O'Leary, 1992; Ghosh and Shatz,
1992, 1993; Allendoerfer and Shatz, 1994). It is conceivable that
heterotopic neurons, deprived of the normal influence of subplate
cells, could fail to locate or recognize their synaptic partners.
However, despite their heterotopic placement, cortical neurons in the
tish rat establish relatively normal afferent and efferent connections
(Schottler et al., 1998). These findings reinforce the concept that the
relative positioning of subplate cells and cortical plate cells is a
rather flexible determinant of regional connectivity in the cortex
(Caviness and Yorke, 1976; Steindler and Colwell, 1976; Simmons et al.,
1982; Caviness and Frost, 1983; Terashima et al., 1983, 1985; Jensen
and Killackey, 1984; Frost et al., 1986; Caviness et al., 1988).
The absence of Cajal-Retzius cells in the heterotopic tish cortex
could also affect neuronal organization. During normal cortical development, reelin production in Cajal-Retzius cells is part of a
signaling cascade that helps establish proper cortical lamination (D'Arcangelo et al., 1995; Ogawa et al., 1995). Disturbances in this
cascade, which may occur after mutations in the
reelin, mouse disabled 1 (mdab1), p35, or
cdk5 genes, are thought to contribute to cortical lamination
errors (D'Arcangelo et al., 1995; Ogawa et al., 1995; Ohshima et al.,
1996; Chae et al., 1997; Ware et al., 1997). Animals with mutations of
these genes exhibit an inverted lamination of the neocortex (Falconer,
1951; Caviness and Sidman, 1973; Caviness, 1976, 1982; Sweet et al.,
1996; Gonzalez et al., 1997). In the case of the reeler
mutation, this phenotype results from an error in neuronal migration in
which later-generated cells fail to migrate past earlier-generated
cells (Caviness and Sidman, 1973; Caviness, 1982). The misplacement of
cells in the tish cortex could conceivably be caused by an error in
this signaling cascade as well. However, the structural malformations
in the tish rat differ from those of the reeler, scrambler, and
p35-deficient mutant mice in several respects. First, the normotopic
cortex of the tish rat exhibits typical lamination, rather than an
inversion of lamination. Second, the tish malformation is restricted to only part of the neocortex, whereas the malformations in the other mutants are present in multiple brain regions. Third, the tish rat does
not exhibit a generalized defect in the ability of later-generated cells to migrate past earlier-generated cells. Later-generated cells
appear to migrate past earlier-generated cells in both the normotopic
and heterotopic cortices of the tish rat. Although different influences
on the same signaling cascade cannot be ruled out, these findings
suggest that the mechanisms responsible for forming cortical
heterotopia in the tish rat differ from those involved in the formation
of an inverted cortex in the reeler, scrambler, and p35 mutant mice.
The relation between cortical heterotopia in tish rats and SBH in
humans warrants consideration. The structural similarities between
these two entities are substantial (Barkovich et al., 1989; Lee et al.,
1997; Ross et al., 1997). Both are large, bilateral areas of
heterotopic gray matter that typically do not extend into the temporal
lobe. A thick band of white matter separates the heterotopia from
underlying structures, whereas a thinner band of white matter separates
the heterotopia from the overlying neocortex. The overlying neocortex
retains relatively normal patterns of cellular organization, whereas
the heterotopic cells fail to laminate and orient properly. Finally,
both tish rats and human SBH patients are prone to exhibit seizures
(Barkovich et al., 1989; Lee et al., 1997). Thus, these two disorders
bear significant similarities. However, an important feature that
differentiates these disorders is their pattern of inheritance. The
tish phenotype is inherited as an autosomal recessive trait (Lee et
al., 1997), whereas the human SBH syndrome derives from the X-linked
gene doublecortin (Pinard et al., 1994; Dobyns et al., 1996;
des Portes et al., 1997, 1998; Ross et al., 1997; Gleeson et al.,
1998). This difference in chromosomal loci suggests several
possibilities, including the following: (1) the same gene is affected
in the two disorders, but it is present on different chromosomes in the rat and the human; (2) different genes are affected in the two disorders, but both gene products are essential elements in the same
signaling cascade; and (3) different genes are affected and the
fundamental mechanisms responsible for forming the heterotopia are
different for the two disorders. The initial possibility is unlikely
for at least two reasons. First, there exists an extremely high degree
of conservation of loci on the X chromosome among mammals. Second, the
human syndrome of SBH is observed primarily in females, whereas
affected males exhibit a different phenotype with more profound
lissencephaly. Because the mutation in the tish rat breeds true as an
autosomal recessive, and the profound lissencephalic phenotype is not
observed in this animal, it is improbable that the same gene is
responsible for the tish rat and human SBH syndromes. The most likely
explanation is that two different genes are responsible for the two disorders.
In conclusion, the complex sequence of events required for the
development of the neocortex contributes to a surprisingly high
incidence of structural malformations in the human brain. Disorders in
neuronal proliferation, migration, and programmed cell death
undoubtedly play critical roles in many of these anomalies. The present
findings in the tish rat suggest a role for misplaced mitotic activity
in the development of certain cortical malformations. Heterotopic
neurogenesis may be particularly important in the formation of major
neocortical malformations (i.e., periventricular heterotopia, band
heterotopia, double cortex, and cortical tubers), in which large
collections of heterotopic cells underlie the neocortices of epileptic
and mentally retarded individuals.
| |
FOOTNOTES |
Received June 19, 1998; revised Sept. 8, 1998; accepted Sept. 8, 1998.
This work was supported by National Institutes of Health Grant NS34124.
We thank Dr. Masaharu Ogawa of the Kochi Medical School for kindly
providing the CR-50 antibody. We thank Natalie Harrison for excellent
technical assistance.
Correspondence should be addressed to Kevin S. Lee, Box 420 HSC,
University of Virginia, Charlottesville, VA 22908.
| |
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Abstract
Introduction
