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The Journal of Neuroscience, November 1, 2002, 22(21):9352-9357
Miswiring of Limbic Thalamocortical Projections in the Absence of
Ephrin-A5
Daniela
Uziel1, 2,
Sven
Mühlfriedel1,
Kostas
Zarbalis3,
Wolfgang
Wurst3,
Pat
Levitt4, and
Jürgen
Bolz1
1 Universität Jena, Institut für
Allgemeine Zoologie und Tierphysiologie, 07743 Jena, Germany,
2 Programa de Neurobiologia, Instituto de Biofísica
Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21949-590 Rio de Janeiro, Brazil, 3 Max-Planck-Institut für
Psychiatrie, 80804 Munich, Germany, and 4 Department of
Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania 15261
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ABSTRACT |
Axon guidance cues of the ephrin ligand family have been
hypothesized to regulate the formation of thalamocortical connections, but in vivo evidence for such a role has not been
examined directly. To test whether ephrin-mediated repulsive cues
participate in sorting the projections originating from distinct
thalamic nuclei, we analyzed the organization of somatosensory and
anterior cingulate afferents postnatally in mice lacking ephrin-A5 gene
expression. Projections from ventrobasal and laterodorsal nuclei to
their respective sensory and limbic cortical areas developed normally. However, a portion of limbic thalamic neurons from the laterodorsal nucleus also formed additional projections to somatosensory cortical territories, thus maintaining inappropriate dual projections to multiple cortical regions. These results suggest that ephrin-A5 is not
required for the formation of normal cortical projections from the
appropriate thalamic nuclei, but rather acts as a guidance cue that
restricts limbic thalamic axons from inappropriate neocortical regions.
Key words:
wiring molecules; axonal guidance; cortical development; limbic system; thalamocortical circuits; ephrin
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INTRODUCTION |
The cerebral cortex is parceled into
functional areas that have specific patterns of input and output
projections. The medial cortical areas (prefrontal, cingulate, and
retrosplenial cortices), which are part of the limbic system, receive
afferents from the mediodorsal group and laterodorsal thalamic nuclei
(Domesick, 1972 ; Van Groen and Wyss, 1992), whereas neocortical areas,
such as the somatic sensorimotor cortex, receive afferents from the ventrolateral group of nuclei (Fabri and Burton, 1991 and references therein). This precise areal organization occurs from the initiation of
the projection during development. Thus, thalamic afferents normally
bypass nontarget regions to innervate their appropriate cortical
targets (Wise and Jones, 1978; Crandall and Caviness, 1984; De Carlos
and O'Leary, 1992; Agmon et al., 1995). It has been suggested that
guidance molecules may regulate the early specificity (Barbe and
Levitt, 1992; Bolz and Götz, 1992; Mann et al., 1998;
Molnár and Blakemore, 1991, 1995). For example, during normal
development, limbic cortical areas express the limbic system-associated
membrane protein (LAMP), a cell adhesion molecule that has been shown
to act as a guidance and branch signal for thalamic axons in
vivo and in vitro (Barbe and Levitt, 1992; Mann et al.,
1998). Several authors demonstrated that the tyrosine kinase receptor
ligand ephrin-A5 is expressed in the somatosensory cortex at a
embryonic time period when thalamic fibers invade the cortex and that
one of its receptors, EphA5, is expressed in the medial group of
thalamic nuclei that normally project to limbic cortex (Gao et al.,
1998, Mackarehtschian et al., 1999; Vanderhaeghen et al., 2000). The
expression patterns are consistent with ephrin-A5 acting as a repulsive
cue for limbic thalamic axons, similar to their role in regulating
topographic retinotectal (Cheng et al., 1995; Drescher et al., 1995,
1997), hippocampal (Stein et al., 1999; Brownlee et al., 2000), and
thalamocortical (Vanderhaeghen et al., 2000) projections.
In agreement with this hypothesis, ephrin-A5 inhibits in
vitro the outgrowth of neurites from medial (limbic) thalamic
neurons but has no effect on lateral (nonlimbic) thalamic
neurons (Gao et al., 1998). In addition, it acts as a
repulsive axonal guidance signal for limbic thalamic axons, whereas for
most nonlimbic thalamic fibers, it exhibits no guidance activity (Mann
et al., 2002). To test this proposed guidance role more directly, we
examined the targeting of thalamocortical projections in the absence of ephrin-A5 using a gene-targeted mouse line in which the ephrin-A5 transcript and protein are absent (Knöll et al., 2001). Our
findings suggest that ephrin-A5 contributes to the precision of
developing cortical circuitry by repelling limbic thalamic axons to
prevent penetration into neocortical areas.
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MATERIALS AND METHODS |
Thirteen wild-type (+/+) and 20 ephrin-A5
knock-out ( /) animals were used in this study. Ephrin-A5 / mice
are the same described by Knöll et al. (2001). At postnatal day 8 (P8) (day of birth is P0) animals were perfused with 4%
paraformaldehyde, and the brains prepared for standard
1,1'-dioctadecyl-3, 3, 3', 3'-tetramethylindocarbocyanine
perchlorate (DiI) (Molecular Probes, Eugene, OR) labeling as
described previously (Novak and Bolz, 1993). Crystals were inserted
into different rostrocaudal levels of the anterior cingulate or primary
somatosensory cortex. In some cases, 4-(4-(dihexadecylamino)
styryl)-N-methylpyridinium iodine (DiASP) (Molecular Probes)
was used for double labeling. Vibratome sections (100 µm) were
mounted for visualization on a Zeiss (Oberkochen, Germany)
Axiovert or a Nikon (Tokyo, Japan) E800 fluorescence microscope. The
thalamic nuclei were identified according to their rostrocaudal and
ventrodorsal position, comparing DiI-labeled slices counterstained with
4',6'-diamidino-2-phenylindole dihydrochloride with 25 µm
cresyl violet-stained sections of P8 animals and with an anatomical
mouse atlas (Franklin and Paxinos, 1997). The investigators
were blind to the genotype until after initial examination and mapping.
All cases were excluded in which crystals entered subcortical white
matter, which resulted in intensively labeled corticocortical fibers.
All sections were photographed at various magnifications, and, in most
cases (eight ephrin-A5 +/+ and 12 ephrin-A5 /), the
number of cells in each thalamic nucleus in all sections was
counted (Table 1) and plotted on charts
(see Figs. 3, 4). The percentage of misrouted cells was calculated as
number of cells identified in the laterodorsal nucleus of the thalamus
(LD) plus the cells in the lateroposterior nucleus (LP) divided by the
number of retrogradely labeled cells in the ventrobasal complex (VB).
Because the posterior nucleus of the thalamus (Po) projects to both
anterior cingulate and parietal cortices, it was not possible to
identify putative misrouted cells in this nucleus. Statistical
significance between genotypes was determined using the Mann-Whitney
U test.
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Table 1.
Number of retrogradely labeled neurons in different
thalamic nuclei after injection of lipophylic tracers in sensorimotor
(A-I, M-P) and cingulate cortex (J-K, O-T) in normal (M-T) and
ephrin-A5 knock-out (A-L) mice
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RESULTS |
Diffusion of DiI or DiASP from cortical injection sites resulted
in readily visible fibers along their pathway in the white matter and
internal capsule and retrogradely labeled cells in different thalamic
nuclei. Analysis of cresyl violet-stained sections revealed normal
cytological organization of the cerebral cortex and thalamic nuclei of
ephrin-A5 / animals (Fig.
1A,B).
Implantation of crystals along the anterior cingulate cortex resulted
in expected intense labeling of neurons in dorsal thalamic regions,
including LD and LP nuclei. The pattern of labeling was identical in
both +/+ and / mice. Cingulate injections also labeled
neurons in a region ventral to LD, corresponding to the Po. Crystals
localized more rostrally in the anterior cingulate/prefrontal cortex
boundary also labeled axons from the anterior and medial thalamic
group, as described previously (Domesick, 1972, see cases Q-T). Table 1 illustrates the number of retrogradely labeled cells in each nucleus
of +/+ (Table 1, Q-T) and / animals (Table 1, J-L), with a similar degree of labeling in both genotypes. We did not identify even a single case in which abnormal or ectopic cells were
found in the thalamus of ephrin-A5 / animals after implantation of
DiI in the anterior cingulate cortex.
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Figure 1.
Low-power photomicrographs of coronal brain
sections from wild-type (A, C) and
ephrin-A5 knock-out (B, D) animals after
implantation of DiI in the sensorimotor cortical region of P8 mice.
A and B show bright-field photographs of
the slices labeled with DiI (left) and cresyl violet
staining for identification of the thalamic nuclei
(right). C and D
correspond to the marked areas in A and
B, and the dashed line indicates the
border between hippocampus and dorsal thalamus. Note that, in
C, cells are concentrated in ventral portions of the
thalamus, a region corresponding to Po and VB. In D,
after placement of DiI in a cortical region similar to
C, cells are stained not only in the Po/VB region but
also dorsally in LD; some of these cells are indicated by an
arrow. Scale bars: A,
B, 200 µm; C, D, 100 µm.
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Dye crystals placed in the somatic sensorimotor region of
+/+ mice resulted in a large number of retrogradely labeled
cells ventral and laterally in the thalamus, in the region
correspondent to Po and the VB (Table 1, M-P; Fig. 1C; see
Fig. 4). In rare instances, one or two cells were present in dorsal and
posterior regions of the thalamus, corresponding to LP. Figure 3
depicts a representative case (Table 1, brain A) showing both the
injection site and charts of three of eight sections with retrogradely
labeled cells. The extent and patterns of labeling of VB and Po were
obtained in the ephrin-A5 / mice (Table 1, A-I), but, in addition,
clusters of dorsally located cells were retrogradely filled after
implantation of DiI in the sensorimotor cortex of ephrin-A5 / mice
(Figs. 1D,
2A,B).
The ectopic cells were identified in 90% of the cases studied, with a
range in the extensiveness of the retrograde labeling (Table 1). These
cells typically occupied more anterior parts of the dorsal thalamus,
which corresponds anatomically to LD, although some cells were also
found more caudally in LP. Most of these labeled cells were localized
in a region between interaural 2.34, bregma 1.46 and interaural 2.10, bregma 1.70 (sections represented in Figs.
3, 4).
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Figure 2.
Low-power (A) and high-power
(B) photomicrographs of ectopic-labeled cells in
dorsal thalamus of knock-out animals after implantation of DiI in the
sensorimotor cortex. C, For comparison, retrogradely
labeled neurons in the same thalamic region after placement of
DiI in the cingulate cortex of normal animals. The dashed
line indicates the border between hippocampus and dorsal
thalamus. See Figure 1. Scale bars: A, 100 µm;
B, C, 50 µm.
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Figure 3.
Thalamocortical projections in an
ephrin-A5-deficient animal. A, Tracer injection site;
DiI crystals in the somatosensory cortex were confined to two
consecutive 100-µm-thick sections. B-D, Charts of
sections with retrogradely labeled cells in the thalamus and
thalamocortical axons extending through the internal capsule. Scale
bars: A, 1 mm; (in D)
B-D, 500 µm.
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In the double labeling experiments of ephrin-A5 / mice, in which
different crystals of carbocyanine dyes
were introduced simultaneously in the anterior cingulate (DiASP) and
sensorimotor (DiI) cortices, DiI-labeled cells were identified among
DiASP-labeled ones in LD, LP, and Po (Fig. 4). Although there was an
obvious anatomical overlap of the two populations, double-labeled cells were never identified. Morphologically, the ectopic thalamic neurons after sensorimotor cortex labeling in the / mice exhibited large dendritic arbors, very similar to ones obtained after implantation of
crystals of DiI in the anterior cingulate cortex (Fig. 2) and reported
previously in tissue graft studies of developing limbic cortex (Barbe
and Levitt, 1992). A schematic summary of the present results is
presented in Figure 5.
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Figure 4.
Double-labeling experiments. Retrogradely stained
thalamic neurons after implantation of DiASP in the cingulate cortex
(open squares) and DiI in the sensorimotor region
(filled squares). Composite drawings from three
experiments. Left, Wild type; right,
ephrin-A5 knock-out mice. A, interaural 2.23, bregma
1.46; B, interaural 1.86, bregma 1.95. Note that, in
the absence of ephrin-A5, a group of limbic thalamic cells are miswired
and innervate the sensorimotor cortex. VPL, Ventral
posterolateral nucleus; VPM, ventral posteromedial
nucleus.
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Figure 5.
Schematic representation of thalamocortical
projections in wild-type (left) and ephrin-A5 /
(right) mice. Thalamic neurons in ventrobasal nuclei
(red circle) project to the sensorimotor cortex
(red ellipse), and limbic thalamic neurons in
laterodorsal nuclei (green circle) project to the
cingulate cortex (green ellipse). However, in
knock-out animals, limbic thalamic neurons also formed additional
projections to the sensorimotor cortex (indicated by red-green
lines on the right). The portion of miswired
cells was variable (see Table 1) and is overrepresented in this
schematic figure. These data suggest that ephrin-A5 acts as a repulsive
guidance cue that restricts limbic thalamic axons from innervating
inappropriate cortical regions.
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DISCUSSION |
The present analysis of the developmental topography of
thalamocortical projections in the absence of a putative guidance molecule, ephrin-A5, demonstrates that thalamic afferents avoid certain
territories because of the presence of local repulsive cues
distributed regionally in the cerebral cortex. The role of the cortex
in providing information for establishing specific connections and
determination of anatomical and functional areal characteristics has
been a subject of controversy. In the last few years, a variety of
experimental strategies have been used to produce strong evidences that
the cortex participates in a particularly instructive manner in
establishing areal phenotypes that ultimately regulate afferent
organization (Barbe and Levitt, 1992; Bolz and Götz, 1992; Mann
et al., 1998; Nakagawa et al., 1999; Bishop et al., 2000; Vanderhaeghen
et al., 2000; Hevner et al., 2001). This has been shown most recently
in mutant mice in which deletion of dorsal telencephalic transcription
factors emx2, pax6, or lhx2 resulted
in aberrant expression of guidance molecules and errors in
thalamocortical projections (Porter et al., 1997; Götz et al.,
1998; Bishop et al., 2000; Mallamaci et al., 2000; Fukuchi-Shimogori
and Grove, 2001). Although functional significance of the misexpressed
axon guidance molecules has been inferred, direct assessment of the
consequences of disrupted or absent molecular cues in vivo
had not be investigated directly.
Methodological considerations
Our data indicate that the LD-labeled neurons in the ephrin-A5
/ mice, after neocortical labeling, represents errors in axon
targeting. There are several reasons to support this conclusion. First,
tracer injections in other somatic sensorimotor cortices, such as the
posterior parietal cortex (PPC), label cells mostly in the lateral
posterior nucleus, with very few neurons labeled in LD (Chandler et
al., 1992; Reep et al., 1994). Injections rostral to PPC never label
neurons retrogradely in LD and LP, but rather, only neurons in VB and
Po. This is the specific region that we targeted in our studies
avoiding contamination of PPC with the dye. The site of implantation of
the dye crystals were very similar between ephrin-A5 +/+ and / mice.
Although 9 of 10 ephrin-A5 / mice had ectopically labeled cells in
LD, there was interanimal variability in the percentage of ectopic
cells. This variability is most likely attributable to the position and
depth of the crystal placement in the cortex. In case D, for example,
in which we failed to identify ectopic neurons in LD, there were
substantially fewer cells labeled in VB when compared with other cases
with injections in the somatosensory region. This case had a more
superficial placement of the DiI crystal, thus producing incomplete
labeling of layer 4 and resulting in an overall decrease in thalamic
labeling. However, in cases B and E, a similar number of cells were
labeled in VB and Po, but there was a more than fivefold difference in
the number of miswired cells in LD. Thus, there also may be some
variability in the penetrance of the phenotype between different animals.
A role for repulsive guidance cues in cortical development
There are a number of putative guidance molecules expressed in the
embryonic cortex at the time thalamic axons arrive and thus could
influence targeting and innervation of specific cortical areas. Gao et
al. (1998) demonstrated in vitro that ephrin-A5 inhibited
outgrowth of EphA5-expressing medial (limbic) thalamic neurons but not
lateral (sensory) neurons. They first suggested that ephrin-A5 in the
somatosensory region of developing mice could help guide medial
thalamic axons to their correct cortical limbic targets. Recently,
Vanderhaeghen et al. (2000) showed that ephrin-A5 influences the
development of the barrel field in mice. Fibers originating from the
medial part of the VB of the thalamus, which is poor in EphA4,
innervate the most medial part of the barrel field, rich in ephrin-A5.
Lateral VB regions, rich in EphA4 innervate lateral cortical regions,
which are poor in ephrin-A5. In ephrin-A5 knock-out mice, although the
topography map of the posteromedial barrel subfield is not
altered, there is an abnormality in the size of the barrels; medial
barrels are compressed and lateral barrels are expanded in area. These
findings suggest that ephrin-A5 also could act as a positional label
for map formation.
Mackarehtschian et al. (1999) reported that expression of ephrin-A5,
detected by in situ hybridization, occurs in the rat cortex
on embryonic day 17 (E17), 1 d after the arrival of thalamic fibers in the cortex. Based on these findings, the authors suggest that
it is unlikely that ephrin-A5 guides the initial innervation of
anterior and lateral regions of the cortex. Instead, this molecule could repel later-arriving thalamic axons from already innervated areas. Although this conclusion is still consistent with our findings, the timing of expression of sufficient biologically active protein is
difficult to determine using in situ hybridization, which is not particularly sensitive for detecting low levels of transcript.
Ephrin-A5 controls errors in limbic axon targeting
We show here that ephrin-A5 knock-out mice have abnormalities in
the innervation of the cortex by thalamic afferents. Although most of
LD cells from ephrin-A5 / mice correctly innervate the medial
limbic cortex, a non-overlapping subpopulation of LD neurons have
misrouted axons, reaching neocortical areas. LD normally has dense
projections to retrosplenial granular cortex, presubiculum and
parasubiculum, and more modest innervation of cingulate cortex (Van
Groen and Wyss, 1990, 1992). It has been postulated that LD plays a
special role in integrating limbic function from different levels of
the brain with few, if any, projections to the sensorimotor cortex
(Ryszka and Heger, 1979; Barbe and Levitt, 1992 and references therein). We found that apparently separate axons, originating from
different populations of LD neurons, innervate limbic and neocortical
areas in ephrin-A5 / mice. Axons from other thalamic nuclei that
connect limbic areas, such as the anterior nuclear complex and
mediodorsal nucleus, never enter S1 in ephrin / animals. This is
probably attributable to the anatomical organization of thalamocortical
projections. Fibers originating in those nuclei have more rostral
trajectories, whereas fibers from LD exit the thalamus to innervate the
cortex in a similar trajectory as VB fibers (Bernardo and Woolsey,
1987; Van Groen and Wyss, 1992). This confirms the hypothesis that the
expression of ephrin-A5 in the cortex is important for limbic axons to
avoid errors in targeting. Our study does not address the timing of
when the misrouting occurs, which will be important to determine to
understand the underlying cause for only a subpopulation of neurons
exhibiting mistargeting.
Multiple guidance cues control thalamic axon targeting
Our data also are consistent with multiple molecules participating
in the targeting of limbic thalamic axons. For example, LAMP is
expressed in limbic cortical areas and in experimental systems and acts
as a positive guidance molecule for thalamic limbic axons (Barbe and
Levitt, 1992; Mann et al., 1998). Thus, LAMP and other potential
molecular cues, such as cadherins, could provide sufficient information
for normal limbic thalamic axon targeting in the ephrin-A5 /
cortex. It is possible that other ephrin ligands and receptors also
could participate in the guidance of thalamocortical projections.
However, ephrin-A4 is not expressed in the cortex at E17, and the
pattern of distribution of ephrin-A3 is uniform in the cortical plate,
with no apparent gradients or areal specificity (Mackarehtschian et
al., 1999). Thus, it is unlikely that either of these ephrin family
members contributes to the selective innervation of cortical areas, as
we demonstrate for ephrin-A5. Gale et al. (1996) showed, however, that
there is considerable promiscuity in receptor-ligand binding in this tyrosine kinase family. Thus, it is possible that other receptors, such
as EphA3 and EphA4, could interact with ephrin-A5. However, these two
receptors are expressed medially, dorsally, and ventrally in the
thalamus. Only EphA5 has a much higher medial and dorsal expression and
very low levels ventrally in the thalamus, consistent with medial axons
avoiding domains of ephrin-A5 expression (Gao et al., 1998).
From the present study, it is clear that ephrin-A5 works in concert
with other wiring molecules in the targeting of thalamocortical projections. The role of multiple cues will be tested shortly as
additional mouse lines with targeted deletion of genes that encode
putative guidance molecules become available. We predict that a
combinatorial deletion of cues will result in a more severe phenotype,
in which ectopic projections form with a much reduced normal thalamic
innervation pattern.
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FOOTNOTES |
Received May 2, 2002; revised July 12, 2002; accepted July 22, 2002.
This work was supported by National Institutes of Mental Health Grant
MH45507 (P.L.) and the Interdisziplinäres Zentrum für Klinische Forschung Jena (J.B.). D.U. is a fellow from the
Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior Foundation of Brazil.
Correspondence should be addressed to Dr. Jürgen Bolz,
Universität Jena, Institut für Allgemeine Zoologie und
Tierphysiologie, Erbertstrasse 1, 07743 Jena, Germany. E-mail
bolz{at}pan.zoo.uni-jena.de.
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ABSTRACT
INTRODUCTION
