|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online January 12, 2006
doi: 10.1242/10.1242/dev.02209
1 Department of Neurobiology, Pharmacology and Physiology, University of
Chicago, Chicago, IL 60637, USA.
2 Division of Morphogenesis, Institute of Molecular Embryology and Genetics
(IMEG), Kumamoto University 2-2-1 Honjo, Kumamoto, Kumamoto 860-0811,
Japan.
3 Department of Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, CO 80309, USA.
* Authors for correspondence (e-mail: egrove{at}bsd.uchicago.edu; myoshida{at}kaiju.medic.kumamoto-u.ac.jp)
Accepted 10 November 2005
 |
SUMMARY |
|---|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Key words: Mouse, Cajal-Retzius cells, Neocortex
|
INTRODUCTION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
;
Rakic, 1974) requires the
secreted glycoprotein reelin (D'Arcangelo
et al., 1995; Ogawa et al.,
1995; Rice and Curran,
2001). In reeler mice, which lack functional reelin,
neocortical layers are inverted and cells are abnormally dispersed
(Caviness, 1982;
Caviness and Sidman, 1973;
D'Arcangelo et al., 1995;
Goffinet, 1984). Similar
defects are seen in mice lacking the reelin receptors very-low-density
lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (Apoer2; Lrp8
– Mouse Genome Informatics)
(Hiesberger et al., 1999;
Trommsdorff et al., 1999), or
the downstream intracellular adaptor protein Dab1
(Howell et al., 1997;
Sheldon et al., 1997;
Ware et al., 1997). Targets of
reelin signaling, expressing both receptors and Dab1, include migrating
neurons themselves (Perez-Garcia et al.,
2004) and the radial glial cells
(Hartfuss et al., 2003;
Luque et al., 2003), which
serve both as guides for migration and as neuronal progenitor cells
(Noctor et al., 2001).
A core question remains unanswered: how does reelin influence migrating
neocortical neurons so that they settle in distinct layers from deep to
superficial? The functions proposed for reelin include: instructing migrating
neurons to leave their glial guides and stop migration, forming a graded
signal from the MZ that positions neuronal cell bodies in the cortical plate
(CP) (Luque et al., 2003;
Rice and Curran, 2001); or
simply allowing neurons to pass other cells that have settled along their
migratory route (Caviness,
1982; Pinto-Lord et al.,
1982). One way to test these and other diverse ideas is to
determine where the supply of reelin needs to be with respect to migrating
neocortical neurons. If reelin is a guidance or positional signal, for
example, then sources are likely to be required at specific sites. If reelin
is a permissive or enabling signal, the precise source may not matter.
Since the identification of reelin, and the observation that it is robustly
produced by Cajal-Retzius (CR) cells in the marginal zone (MZ) of the cortical
primordium (D'Arcangelo et al.,
1995; Meyer et al.,
1999; Ogawa et al.,
1995), CR neurons have been thought to be essential for laminar
organization (Bielas et al.,
2004; Rice and Curran,
2001). CR cells are strategically located, close to the pial
end-feet of radial glia, at the end of the radial migratory pathway of
neocortical pyramidal cells (Alcantara et
al., 1998; Hartfuss et al.,
2003; Luque et al.,
2003). Reelin can signal to both radial glial cells and their
daughter neurons (Luque et al.,
2003; Magdaleno et al.,
2002), potentially providing guidance for neurons throughout
migration.
Much indirect evidence further supports a central role for CR cells in
establishing neocortical layer pattern. For example, the neurotrophin BDNF
regulates reelin in CR cells. BDNF overexpression reduces reelin in CR cells,
and neocortical abnormalities include laminar defects that resemble those in
the reeler mouse (Ringstedt et
al., 1998). However, low levels of reelin mRNA (Reln) are
expressed elsewhere in the cortical primordium
(Alcantara et al., 1998;
Meyer et al., 2002), and
because most manipulations of CR cells are also general manipulations of
reelin signaling, there is little direct evidence that CR cells themselves are
absolutely required. Local application of a toxic agent to newborn mouse
cortex ablates CR cells and disrupts cell migration to layers II/III
(Super et al., 2000), but this
approach might affect other cell types that regulate migration. In particular,
meningeal cells maintain trophic interactions with CR cells, and themselves
contain neuronal guidance molecules
(Halfter et al., 2002;
Hartmann et al., 1992;
Lu et al., 2002;
Super et al., 1997).
New evidence indicates that some steps in cortical histogenesis can take
place without a reelin signal from CR cells in the MZ. In wild type, but not
reeler mice, neurons form the CP by invading the preplate, separating
its two main components, the MZ and subplate
(Caviness, 1982;
Luskin and Shatz, 1985;
Stewart and Pearlman, 1987).
In vitro, a specific fragment of reelin, applied in culture to slices from
reeler telencephalon, provides a partial rescue of preplate
partition, permitting the formation of a near-normal CP
(Jossin et al., 2004).
Furthermore, in reeler mice, forced reelin expression under the
control of the nestin promotor (nestin-reelin), fully rescues this
component of the reeler phenotype
(Magdaleno et al., 2002).
Driven by the nestin promotor, reelin is expressed in the ventricular zone
(VZ), but presumably also throughout the radial glial progenitor cells that
express nestin and span the cortical primordium. Radial glial expression of
reelin is not sufficient, however, to rescue normal layer patterning of the
CP. Higher levels of reelin, delivered from the endogenous CR cell source,
would seem to be required (Magdaleno et
al., 2002).
Further studies, however, question even this requirement for CR cells
(Meyer et al., 2004;
Meyer et al., 2002;
Yang et al., 2000). CR cells
express p73 (Trp73 – Mouse Genome Informatics), a protein with isoforms
that differentially affect apoptosis
(Meyer et al., 2004;
Pozniak et al., 2002;
Yang et al., 2000). In
p73-deficient mice, CR cells die, but neocortical layering is not inverted
(Meyer et al., 2004;
Yang et al., 2000). Perhaps,
however, CR cells initiate normal lamination before their early death by
apoptosis. CR cells are missing in p73 mutants at E12.5
(Meyer et al., 2004), but are
already present in the MZ by E10.5
(Alcantara et al., 1998). In
the present study, we determined directly if CR cells in the neocortical MZ
are the crucial source of reelin for neocortical layer patterning. To do so,
we took a genetic approach to delete the progenitors of neocortical CR
cells.
|
MATERIALS AND METHODS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
), an
Otx1-Cre mouse line (gift of Philippe Soriano, Fred Hutchinson Cancer
Research Center, and Flora Vaccarino, Yale), and the two mouse lines generated
for this study: Wnt3a-IRES-Cre and Wnt3a-IRES-xneox-dt-a.
All mice were bred and maintained in compliance with National Institutes of
Health guidelines. The University of Chicago IACUC approved the animal
protocols used in this study.
Generation of mice to fate map the hem
In the telencephalon, the Wingless-Int gene Wnt3a is
expressed only in the cortical hem, and is not expressed after birth in other
cell types (Lee et al., 2000b;
Shimogori et al., 2004).
Consequently, the Wnt3a locus is ideal for genetic fate mapping and
ablation of the hem. To fate map the hem Cre recombinase was inserted
into the 3' end of the Wnt3a locus, using standard homologous
recombination in ES cells. An IRES preceding Cre permitted expression
of both Wnt3a and Cre proteins from the same mRNA, and no disruption of Wnt3a
activity was detected. That is, mice heterozygous or homozygous for the
Wnt3a-IRES-Cre allele showed none of the striking phenotypic features
of Wnt3a loss of function (Takada et al.,
1994). We did not even detect a sensitive indicator of decreased
canonical Wnt signaling from the hem, namely, a shrunken hippocampal dentate
gyrus (Galceran et al., 2000;
Zhou et al., 2004).
Cell fate mapping
Wnt3a-IRES-Cre mice were crossed with R26R mice. Offspring were
genotyped and mice heterozygous or homozygous for both the R26R and
Wnt3a-IRES-Cre alleles were processed further. An overview of cell
types generated from the hem was obtained by staining whole-mount brains and
sections for ß-gal, using immunohistochemistry or X-gal histochemistry.
Cell type was ascertained with antibodies against GFAP, Olig2, NeuN, reelin,
GABA and p73. Mice were assessed at a range of ages from E10 to P30.
Genetic ablation of the hem
To ablate the cortical hem, a cassette (gift of Kevin Lee and Tom Jessell,
Columbia) carrying an IRES, followed by stop codons flanked by loxP sites,
followed by a cDNA encoding the diptheria toxin subunit A (dt-a)
(Lee et al., 2000a), was
inserted into the 3' end of the Wnt3a locus, again using
standard ES cell technology (Fig.
3A). Mice carrying one such allele were indistinguishable from
wild-type mice, given that activation of the toxin was prevented by the stop
codons preceding dt-a (Lee et
al., 2000a). Dt-a was activated in the cortical hem by crossing
mice carrying the Wnt3a-IRES-xneox-dt-a allele with an
Emx1-IRES-Cre mouse line (Gorski
et al., 2002). In mice heterozygous for both alleles, Cre-mediated
recombination occurred selectively in cells that had once expressed both
Emx1 and Wnt3a. In the telencephalon, this was restricted to
the cortical hem. Because the dt-a subunit is not transferred from cell to
cell (Lee et al., 2000a), only
the hem was directly ablated. Control brains, which were of the
Wnt3axneoxdt-a/+; Emx1+/+ genotype, showed an
entirely normal hem. Recombination did occur elsewhere in the body of double
heterozygotes, however, leading to a short lower jaw and an inability of the
mouse pups to suckle. This recombination appeared to be due to an overlap of
Emx1 and Wnt3a expression in neural crest cells headed for
the jaw. Hem-ablated mice consequently died shortly after birth.
Unfortunately, this precluded a systematic birth-dating study of neocortical
layers, given that many neurons will reach their final layer after birth.
Assessing hem loss and its effects
In situ hybridization (Grove et al.,
1998) and immunohistochemistry were used to detect a panel of
molecular markers of the hem, CR cells and other tissues. The hem expresses
both Wnt3a and Wnt2b selectively
(Grove et al., 1998). The
transcription factor gene Lmx1a is expressed along the dorsal midline
of most of the neuraxis, including the hem, and Wnt8b is expressed in
the hippocampal primordium, hem and choroid plexus
(Failli et al., 2002;
Lee et al., 2000b).
Hem-ablated mice were assessed with in situ hybridization and
immunohistochemistry for the presence of reelin- and p73-positive cells
(E10.5, E11.5, E12.5, E13.5, E15.5 and E18.5), preplate splitting (E15.5), and
laminar organization (E18.5). At least six mutant mice were analyzed at each
timepoint. The preplate, MZ and subplate were identified with immunoreactivity
for calretinin and chondroitin sulfate proteoglycans (CSPGs). Developing
layers in neocortex were identified by the laminar-specific expression
patterns of a panel of genes as detailed below.
Testing the meninges covering the neocortical primordium
CR cells are highly sensitive to defects in the overlying meninges, and
each provides trophic support for the other
(Super et al., 2000). Loss of
the meninges covering the neocortical primordium could be a plausible
additional cause of loss of CR cells. The meninges were therefore compared
between hem-ablated and control mice at a range of ages, using morphology and
gene expression of IGF2 and MF-1, a forkhead/winged helix transcription
factor, both expressed in meninges (Kume
et al., 1998). Using these methods, the meninges in the
hem-ablated mice were found to be similar to controls.
Antibodies
To analyze cell and tissue type, the following antibodies were used: rabbit
anti-ß-galactosidase, ICN (Cappel); mouse anti-NeuN (Chemicon, clone
MAB377); mouse anti-reelin (Calbiochem, clone G10); mouse anti-p73 (Neomarker,
clone ER-15); rabbit anti-calretinin (Chemicon); mouse anti-CSPG (Sigma, clone
CS-56); rabbit anti-GABA (Sigma); and rabbit anti-Olig-2 (gift of David
Rowitch, Harvard). Secondary antibodies were from Molecular Probes.
|
RESULTS |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
; Takiguchi-Hayashi et
al., 2004). To confirm and extend these findings with a direct
cell lineage approach, we used the Cre-loxP recombination system, generating a
Wnt3a-IRES-Cre mouse line in which Cre recombinase
(Cre) was inserted into the Wnt3a locus (see Materials and
methods; Fig. 1A). In these
mice, Cre expression in the hem mimicked expression of endogenous
Wnt3a (Fig. 1B,C). To
label Wnt3a-expressing hem cells and their progeny permanently, the
Wnt3a-IRES-Cre line was crossed with R26R reporter mice
(Soriano, 1999), in which
cells express ß-galactosidase (ß-gal) following Cre-mediated
recombination. Because recombination in the telencephalon was confined to the
Wnt3a-expressing hem, both spatially and temporally (see Materials
and methods), cells labeled with ß-gal could be taken as derivatives of
the hem.
|
).
The cortical hem generates CR cells in the neocortical MZ
The MZ contains a variety of cell types
(Jimenez et al., 2003).
However, CR cells are distinguished by their expression of reelin, calretinin
and glutamate (Alcantara et al.,
1998; del Rio et al.,
1995; Meyer et al.,
1999; Ogawa et al.,
1995; Soda et al.,
2003). A lack of GABA discriminates between CR cells and
late-arriving interneurons that express reelin
(Alcantara et al., 1998;
Hevner et al., 2003b;
Meyer et al., 1999;
Soda et al., 2003). Finally,
CR cells, but not interneurons, express p73, which may be the most specific
single marker of CR cells in the MZ (Meyer
et al., 2004; Meyer et al.,
2002). In R26R mice carrying a Wnt3a-Cre allele, almost
all ß-gal-positive cells in the embryonic MZ or in layer 1 of postnatal
cerebral cortex expressed p73 and reelin, but not GABA
(Fig. 2F-K), indicating that
hem-derived MZ cells are CR cells.
|
|
In mice of both genotypes, we determined the percentage of reelin- or p73-positive cells that co-express ß-gal in medial cortex, adjacent to the hem (including the hippocampal primordium), and in dorsolateral neocortex. At E12.5, in heterozygotes, about 60% and 30% of p73-positive cells in the medial and dorsolateral cortex, respectively, were also ß-gal-positive. In homozygotes, in which Cre recombinase is expressed earlier, and presumably at higher levels, these percentages were 90% and 60% (Fig. 2F,G). In both sets of brains, the proportion of hem-derived CR cells was higher in medial cortex, closer to the source. Moreover, the proportion rose at both medial and lateral sites as development proceeded (counts made at E12.5, E15.5 and E18.5), suggesting an ongoing lateral migration from the hem.
Direct cell lineage tracing therefore validates previous suggestions that
the hem is a source of CR cells (Meyer et
al., 2002; Takiguchi-Hayashi
et al., 2004). Most neocortical CR cells are hem derived.
Nonetheless, we found that some reelin-expressing cells in the MZ of both
dorsolateral neocortex and hippocampus were not ß-gal positive. These
might represent CR cells born before Cre recombination, or cells generated
outside the hem (Bielle et al.,
2005). To determine more accurately the proportion of CR cells
derived from the hem, and to explore the function of this cell population, we
ablated the hem genetically.
Genetic ablation of the hem
To ablate the hem, cDNA encoding the diptheria toxin, subunit A (dt-a) was
inserted into the Wnt3a locus (see Materials and methods and
Fig. 3A). Stop codons flanked
by loxP sites preceded dt-a (Fig.
3A) (Lee et al.,
2000a), preventing activation of the toxin in mice carrying the
Wnt3a-xneox-dt-a allele. To remove the stop codons and activate the
toxin, Wnt3a-xneox-dt-a mice were crossed with an
Emx1-IRES-Cre line (Gorski et
al., 2002) that directs Cre recombination in the dorsal
telencephalon. In mice carrying both alleles, dt-a was activated in cells that
had co-expressed Emx1 and Wnt3a, i.e. in the telencephalon,
only in the cortical hem.
Cre-mediated recombination directed by the Emx1-IRES-Cre mouse
begins at E9.5. At E10, almost complete hem ablation was evident by the loss
of characteristic hem expression of Wnt3a as well as by tissue loss
(Fig. 3B, left; data not
shown). Wnt8b and Lmx1a are expressed in the hem as well as
adjacent tissues (Failli et al.,
2002; Lee et al.,
2000b); their expression was reduced appropriately
(Fig. 3B, left; data not
shown). At E12.5, Wnt3a and 2b expression were missing,
except in a small caudal remnant of the hem
(Fig. 3B, right; data not
shown), correlating with a region of comparatively weak Cre recombination
(Gorski et al., 2002). By
E12.5, other derivatives of the hem, such as the choroid plexus (cpx) were
also largely missing, although a region of the cpx, probably derived from the
caudalmost hem, was still evident by Lmx1a expression
(Fig. 3B, right).
|
; Hevner et al.,
2003b; Soda et al.,
2003). CR cells also show gene expression of stromal-derived
factor (SDF1) and its receptor, CXCR4 (Lu
et al., 2002; Tissir et al.,
2004). Gene expression of both was lost in the MZ of hem-ablated
mice. These observations strongly support the hem as being the origin of the
great majority of neocortical CR cells.
Titration of CR cell number with partial hem ablation
If the hem provides the majority of neocortical CR cells, then shrinking
the hem should lead to a significant loss of CR cells. To test this,
Wnt3a-IRES-xneox-dt-a mice were crossed with an Otx1-Cre
mouse line. When the latter was crossed with R26R mice, recombination occurred
in a pepper-and-salt fashion in the hem. Accordingly, in mice heterozygous for
Wnt3a-IRES-xneox-dt-a and Otx1-Cre, the hem was present, but
smaller than normal. Correlating with the shrunken hem, many fewer CR cells
appeared in the neocortical MZ, and these were dispersed, rather than forming
a closely packed cell layer (data not shown).
Prominence of other sources of migratory reelin-positive cells
As noted above, additional sources of migratory, Reln-expressing
cells have been reported in the ventral telencephalon, and a `retrobulbar'
zone near the olfactory bulb (Gong et al.,
2003; Lavdas et al.,
1999; Meyer et al.,
1998; Meyer and Wahle,
1999). Genetic techniques have recently clarified the location and
contribution of these sources. CR cells that migrate into olfactory and
rostromedial cortex arise from Dbx1-expressing progenitor cells in or
near the septum – perhaps equivalent to the retrobulbar zone – and
at the boundary between dorsal and ventral telencephalon
(Bielle et al., 2005).
Both zones stood out in the absence of hem-derived CR cells in the neocortex. Reln was densely expressed ventral to neocortex, and surrounding the developing olfactory bulb (Fig. 4F,H). From both regions, at E12.5, some Reln-expressing cells (Fig. 4F,H) appeared to move into the CR cell-depleted neocortex. A possibility, therefore, is that other sources supplied CR cells to the hem-ablated neocortex, at least during some periods of embryonic development.
To test this possibility, we examined hem-ablated embryos harvested on E10, E11.5, E12.5, E13.5, E15.5 and E18.5, the day before birth. Reln-expressing cells, probably derived from the septal/retrobulbar region, or the ventral/dorsal telencephalic boundary, were detected in rostromedial and caudomedial cortex at E13.5 (Fig. 5B,I,J), but not at E15.5 or later (Fig. 5K). Moreover, no p73 was expressed in medial cortex (Fig. 5B,C), suggesting that these transient cells were not typical CR cells. A few Reln-positive cells also appeared to scatter into the lateral neocortical MZ from the dorsal-ventral telencephalic boundary (Fig. 5D), but these remained very sparse compared with Reln-expressing CR cells in the same region of control neocortex (Fig. 5E). In brains sectioned at E12.5 to E15.5, no more than one or two Reln-expressing cells per 40 µm section appeared in lateral neocortex (Figs 5, 6; see Fig. S1 in the supplementary material). The neocortical cells originating early from the septal/retrobulbar area or the ventrodorsal telencephalic boundary may be transient in wild-type neocortex too; alternatively, hem-ablated neocortex may be an inhospitable environment for the migration or survival of these cells. We concluded that in mice lacking a cortical hem, the neocortical MZ, from the onset of corticogenesis to birth, contains few or no cells, either defined CR cells or other cell types, that strongly express Reln.
Low levels of reelin expression in the cortical primordium
In both hem-ablated and control mice, a faint band of Reln
expression could be detected deep in the cortical primordium from about E12.5
(Fig. 5G) to at least E18.5. At
E13.5, Reln expression appeared just beneath the pial surface. At
E15.5 Reln expression was distinguishable in the lower intermediate
zone (IZ), and/or subventricular zone (SVZ)
(Fig. 6C). By E18.5 individual
Reln-expressing cells could be resolved
(Fig. 6D-F), and comparison
with layer-specific gene expression indicated that these cells mostly
overlapped expression of Rorb (the gene encoding RORß)
(Fig. 6D-F), which encodes a
transcription factor found in cells of developing layers IV and V
(Hevner et al., 2003a).
Perinatal expression of Reln has been reported previously in layer V
of the mouse (Alcantara et al.,
1998), as has faint expression at earlier embryonic ages
(Meyer et al., 2004;
Meyer et al., 2002). We could
not detect reelin protein with immunohistochemistry in the CP or IZ/SVZ,
probably because of low protein levels, or reelin diffusion. Indeed, the
levels of Reln mRNA were so low at earlier embryonic ages that they
were not detected in every section (compare
Fig. 5G with
5H,J,K).
|
). As the
cortical plate expands, it develops an inverted layer pattern
(Caviness, 1976;
Caviness, 1982;
Goffinet, 1984;
Pinto-Lord et al., 1982).
In both hem-ablated brains and controls, at E13.5, the preplate was
immunoreactive for the Ca2+-binding protein, calretinin, and
chondroitin sulfate proteoglycans (CSPGs)
(Magdaleno et al., 2002;
Sheppard and Pearlman, 1997)
(Fig. 7A,C). By E15.5 in
control mice, the preplate had split. An upper band of calretinin or CSPG
immunoreactivity marked the CR cells of the MZ and a second lower band marked
the subplate (Fig. 7B,D). In
hem-ablated animals, as in controls, a cortical plate formed above a subplate.
The lower band of immunoreactivity, the subplate, was therefore visible. As
would be expected, the upper band, normally containing CR cells, was not
(Fig. 7B,D).
Preplate partition can be rescued in the reeler mutant by forced
expression of reelin in the VZ (Magdaleno
et al., 2002). We speculated that the preplate splits in
hem-ablated mice because of low levels of reelin in the IZ/SVZ. Forced
expression of reelin in the VZ does not, however, rescue the normal layer
pattern of the neocortex (Magdaleno et
al., 2002). We therefore predicted that hem-ablated mice would
show an inverted layer pattern, as in the reeler mouse, and/or
extensive cell dispersion, as in the reeler+nestin-reelin mouse.
Neocortical lamination in hem-ablated mice
Laminar ordering was assessed in hem-ablated mice with gene expression
markers that discriminate among developing neocortical layers
(Hermans-Borgmeyer et al.,
1998; Rubenstein et al.,
1999; Sugitani et al.,
2002). A similar panel of molecular markers was used previously to
show layer inversion in reeler, superimposed on abnormal cell
dispersion (Hevner et al.,
2003a). In control neocortex at E18.5, gene expression of the
transcription factors SCIP (Pou3f1 – Mouse Genome Informatics), SorLA
(Sorl1 – Mouse Genome Informatics), RORß, ER81 (Etv1 – Mouse
Genome Informatics), Fezl and Tbr1, distinguished emerging layers II/III, IV,
V, VI and the subplate (Fig.
7E). To our surprise, hem-ablated mice also showed defined,
correctly ordered layers (Fig.
7F). Expression of each protein in the panel appeared in the same
pial-to-ventricular order as in control neocortex
(Fig. 7E,F). Gene expression
was in some cases more diffuse than in controls, or slightly out of position,
suggesting modest migrational defects (Fig.
7E,F, SorLA/Sorl1 and Tbr1). Thus, precise layer
organization may require a larger complement of CR cells. Nonetheless,
neocortical layers formed in a near normal pattern in the virtual absence of
CR cells and, more specifically, without a strong reelin signal in the MZ.
|
;
Pozniak et al., 2002;
Yang et al., 2000). After
birth, p73 mutants show progressive degeneration of the entire
cerebral cortex, which becomes a thin ribbon of tissue
(Pozniak et al., 2002;
Yang et al., 2000).
|
|
DISCUSSION |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
).
A plausible explanation is that layer order does not depend, as has been
thought, on an abundant, localized source of reelin in the MZ. The
reelin-positive CR cells left in the neocortical MZ of hem-ablated or
p73-null mice (Meyer et al.,
2004) may be sufficient to guide layer position. A more likely
mechanism, given that CR cells are few and far apart in both mutants, is that
compensation occurs by reelin diffusing from subcortical structures or from
other sources inside the cortical primordium.
Indeed, we identified low level reelin mRNA expression in the IZ before the
preplate is split, continuing in the IZ while cells for deeper layers of
neocortex are settling in the CP (Bayer et
al., 1991; Caviness,
1982). Close to birth, Reln expression in layers IV/V
coincides with the migration of layer IV and II/III neurons
(Bayer et al., 1991;
Caviness, 1982). Recent
evidence suggests that the Reln-expressing layer V cells can regulate
the migration of later-born neurons
(Alcantara et al., 2006).
In both hem-ablated and wild-type mice, low level Reln is
therefore expressed below the target layer of migrating neurons, as is the
case for ectopic reelin in the VZ of reeler-nestin-reelin mice. In
each context, neurons must pass through regions of reelin expression to reach
their target layers. Thus, reelin seems not to be acting as a stop,
glial-release or directional signal. Instead, present and recent findings
(Magdaleno et al., 2002;
Meyer et al., 2004) are in
accordance with some of the earliest studies of the reeler mouse
(Caviness, 1982;
Pinto-Lord et al., 1982),
which suggested that neocortical neurons in reeler lost the ability
to push past settled cells that lay in their way. New and classic observations
thus converge on a model in which reelin is a permissive or enabling cue for
migration that is required for the mechanics of movement through cell-dense
tissue.
Birth-dating studies in rats and mice have long shown that although upper
and lower layer cells are largely born at different times, there is
considerable overlap (Hevner et al.,
2003a; Takahashi et al.,
1999). That is, the assembly of layers by timed migration in the
rodent is comparatively rough, and must presumably be refined by other
mechanisms. Interestingly, disruption of reelin signaling also appears to
disrupt layer refinement. In the reeler mutant, inverted layers are
diffuse (Hevner et al.,
2003a). Furthermore, in mice with mutations in other components of
the reelin pathway, neurons for given layers are dispersed but layers are not
always clearly inverted (Howell et al.,
1997; Rice et al.,
1998; Sheldon et al.,
1997). We analyzed reeler neocortex at E18.5, using the
panel of molecular markers cited above, and found that cell dispersion was
more striking than layer inversion (data not shown). In brief, available
evidence suggests that reelin signaling enables migration, and activates other
(more precise) layering mechanisms
(Magdaleno et al., 2002).
Previous studies have implicated CR cells and reelin in layer formation and
connectivity in the hippocampus (Borrell et
al., 1999; Del Rio et al.,
1997). Hem-ablated animals lack a Wnt3a signal from the hem, and
consequently the hippocampus does not develop
(Lee et al., 2000b). Mice
lacking functional p73, however, retain the hippocampus. As noted,
p73-null mice lose almost all CR cells, which depend on p73 for their
survival, but, like hem-ablated mice, show a standard neocortical layer
pattern. By contrast, the hippocampus is highly abnormal. This finding could
be taken to support a requirement for CR cell-derived reelin in hippocampal
morphogenesis. However, at least some hippocampal abnormalities in the p73
mutant are not seen in reeler. Problems in the p73 mutant
hippocampus, particularly in the dentate gyrus, can also be ascribed to the
loss of p73 itself, to defects in the meninges and to the absence of chemokine
signaling mediated by CR cells (Meyer et
al., 2004).
Observations of the p73 mutant hippocampus and neocortex are not,
therefore, in conflict. Moreover, these findings emphasize the complexity of
CR cell signaling. CR cells express a variety of molecules implicated in cell
motility, including Sdf1 (Cxcl12 – Mouse Genome
Informatics) and Cxcr4 (Bagri et
al., 2002; Lu et al.,
2002; Tissir et al.,
2004), and as yet unidentified factors
(Soriano et al., 1997). It
seems likely that CR cells regulate the movement of other cell types, a
conspicuous candidate being the interneurons that migrate into the cortex from
subcortical sites (Hevner et al.,
2004; Stumm et al.,
2003). Because the MZ becomes layer I of neocortex, CR cells are
also well placed to influence dendritic morphogenesis, axon growth and
connectivity within layer I.
Finally, the proposal that layer pattern is rescued in the hem-ablated
mouse by residual reelin is not completely satisfying. Forced reelin
expression in the reeler cortical primordium, for example, does not
rescue layer patterning (Magdaleno et al.,
2002). The complexity of CR cell signaling suggests a new
possibility that would square our findings and those of Meyer and colleagues
(Meyer et al., 2004) with the
mass of evidence that reelin is required for neocortical layering
(Rice and Curran, 2001).
Guidance of neocortical neurons to appropriate layers is likely to involve
several signaling pathways that interact and counterbalance one another. A
hypothesis to be tested, therefore, is that in the absence of reelin, other
migratory cues from CR cells can act unopposed, disrupting a balance in
mechanisms controlling migration and leading to the reeler phenotype.
If CR cells are removed, it is predicted, migration cues remain in balance and
generate a near normal layer pattern.
|
ACKNOWLEDGMENTS |
|---|
|
Footnotes |
|---|
Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/133/3/537/DC1
|
REFERENCES |
|---|
|
TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
|---|
Alcantara, S., Ruiz, M., D'Arcangelo, G., Ezan, F., de Lecea,
L., Curran, T., Sotelo, C. and Soriano, E. (1998). Regional
and cellular patterns of reelin mRNA expression in the forebrain of the
developing and adult mouse. J. Neurosci.
18,7779
-7799.
Alcantara, S., Pozas, E., Ibanez, C. F. and Soriano, E.
(2006). BDNF-modulated spatial organization of Cajal-Retzius and
GABAergic neurons in the marginal zone plays a role in the development of
cortical organization. Cereb. Cortex (in
press)
Angevine, J. B. J. and Sidman, R. L. (1961).
Autoradiographic study of cell migration during histogenesis of cerebral
cortex in the mouse. Nature
192,766
-768.[Medline]
Bagri, A., Gurney, T., He, X., Zou, Y. R., Littman, D. R.,
Tessier-Lavigne, M. and Pleasure, S. J. (2002). The chemokine
SDF1 regulates migration of dentate granule cells.
Development 129,4249
-4260.
Bayer, S. A., Altman, J., Russo, R. J., Dai, X. F. and Simmons,
J. A. (1991). Cell migration in the rat embryonic neocortex.
J. Comp. Neurol. 307,499
-516.[CrossRef][Medline]
Bielas, S., Higginbotham, H., Koizumi, H., Tanaka, T. and
Gleeson, J. G. (2004). Cortical neuronal migration mutants
suggest separate but intersecting pathways. Annu. Rev. Cell Dev.
Biol. 20,593
-618.[CrossRef][Medline]
Bielle, F., Griveau, A., Narboux-Neme, N., Vigneau, S., Sigrist,
M., Arber, S., Wassef, M. and Pierani, A. (2005). Multiple
origins of Cajal-Retzius cells at the borders of the developing pallium.
Nat. Neurosci. 8,1002
-1012.[CrossRef][Medline]
Borrell, V., Ruiz, M., Del Rio, J. A. and Soriano, E.
(1999). Development of commissural connections in the hippocampus
of reeler mice: evidence of an inhibitory influence of Cajal-Retzius cells.
Exp. Neurol. 156,268
-282.[CrossRef][Medline]
Caviness, V. S., Jr (1976). Patterns of cell
and fiber distribution in the neocortex of the reeler mutant mouse.
J. Comp. Neurol. 170,435
-447.[CrossRef][Medline]
Caviness, V. S., Jr (1982). Neocortical
histogenesis in normal and reeler mice: a developmental study based upon
[3H]thymidine autoradiography. Brain Res.
256,293
-302.[Medline]
Caviness, V. S. and Sidman, R. L. (1973). Time
of origin of corresponding cell classes in the cerebral cortex of normal and
reeler mutant mice: an autoradiographic analysis. J. Comp.
Neurol. 148,141
-151.[CrossRef][Medline]
D'Arcangelo, G., Miao, G. G., Chen, S. C., Soares, H. D.,
Morgan, J. I. and Curran, T. (1995). A protein related to
extracellular matrix proteins deleted in the mouse mutant reeler.
Nature 374,719
-723.[CrossRef][Medline]
Del Rio, J. A., Martinez, A., Fonseca, M., Auladell, C. and
Soriano, E. (1995). Glutamate-like immunoreactivity and fate
of Cajal-Retzius cells in the murine cortex as identified with calretinin
antibody. Cereb. Cortex
5, 13-21.
Del Rio, J. A., Heimrich, B., Borrell, V., Forster, E., Drakew,
A., Alcantara, S., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K. et
al. (1997). A role for Cajal-Retzius cells and reelin in the
development of hippocampal connections. Nature
385, 70-74.[CrossRef][Medline]
Failli, V., Bachy, I. and Retaux, S. (2002).
Expression of the LIM-homeodomain gene Lmx1a (dreher) during development of
the mouse nervous system. Mech. Dev.
118,225
-228.[CrossRef][Medline]
Galceran, J., Miyashita-Lin, E. M., Devaney, E., Rubenstein, J.
L. and Grosschedl, R. (2000). Hippocampus development and
generation of dentate gyrus granule cells is regulated by LEF1.
Development 127,469
-482.[Abstract]
Goffinet, A. M. (1984). Events governing
organization of postmigratory neurons: studies on brain development in normal
and reeler mice. Brain Res.
319,261
-296.[Medline]
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N.,
Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E. et
al. (2003). A gene expression atlas of the central nervous
system based on bacterial artificial chromosomes.
Nature 425,917
-925.[CrossRef][Medline]
Gorski, J. A., Talley, T., Qiu, M., Puelles, L., Rubenstein, J.
L. and Jones, K. R. (2002). Cortical excitatory neurons and
glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage.
J. Neurosci. 22,6309
-6314.
Grove, E. A., Tole, S., Limon, J., Yip, L. and Ragsdale, C.
W. (1998). The hem of the embryonic cerebral cortex is
defined by the expression of multiple Wnt genes and is compromised in
Gli3-deficient mice. Development
125,2315
-2325.[Abstract]
Halfter, W., Dong, S., Yip, Y. P., Willem, M. and Mayer, U.
(2002). A critical function of the pial basement membrane in
cortical histogenesis. J. Neurosci.
22,6029
-6040.
Hartfuss, E., Forster, E., Bock, H. H., Hack, M. A., Leprince,
P., Luque, J. M., Herz, J., Frotscher, M. and Gotz, M.
(2003). Reelin signaling directly affects radial glia morphology
and biochemical maturation. Development
130,4597
-4609.
Hartmann, D., Sievers, J., Pehlemann, F. W. and Berry, M.
(1992). Destruction of meningeal cells over the medial cerebral
hemisphere of newborn hamsters prevents the formation of the infrapyramidal
blade of the dentate gyrus. J. Comp. Neurol.
320, 33-61.[CrossRef][Medline]
Hermans-Borgmeyer, I., Hampe, W., Schinke, B., Methner, A.,
Nykjaer, A., Susens, U., Fenger, U., Herbarth, B. and Schaller, H. C.
(1998). Unique expression pattern of a novel mosaic receptor in
the developing cerebral cortex. Mech. Dev.
70, 65-76.[CrossRef][Medline]
Hevner, R. F., Daza, R. A., Rubenstein, J. L., Stunnenberg, H.,
Olavarria, J. F. and Englund, C. (2003a). Beyond laminar
fate: toward a molecular classification of cortical projection/pyramidal
neurons. Dev. Neurosci.
25,139
-151.[CrossRef][Medline]
Hevner, R. F., Neogi, T., Englund, C., Daza, R. A. and Fink,
A. (2003b). Cajal-Retzius cells in the mouse: transcription
factors, neurotransmitters, and birthdays suggest a pallial origin.
Brain Res. Dev. Brain Res.
141, 39-53.[Medline]
Hevner, R. F., Daza, R. A., Englund, C., Kohtz, J. and Fink,
A. (2004). Postnatal shifts of interneuron position in the
neocortex of normal and reeler mice: evidence for inward radial migration.
Neuroscience 124,605
-618.[CrossRef][Medline]
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A.,
Mumby, M. C., Cooper, J. A. and Herz, J. (1999). Direct
binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine
phosphorylation of disabled-1 and modulates tau phosphorylation.
Neuron 24,481
-489.[CrossRef][Medline]
Howell, B. W., Hawkes, R., Soriano, P. and Cooper, J. A.
(1997). Neuronal position in the developing brain is regulated by
mouse disabled-1. Nature
389,733
-737.[CrossRef][Medline]
Jimenez, D., Rivera, R., Lopez-Mascaraque, L. and De Carlos, J.
A. (2003). Origin of the cortical layer I in rodents.
Dev. Neurosci. 25,105
-115.[CrossRef][Medline]
Jossin, Y., Ignatova, N., Hiesberger, T., Herz, J., Lambert de
Rouvroit, C. and Goffinet, A. M. (2004). The central fragment
of Reelin, generated by proteolytic processing in vivo, is critical to its
function during cortical plate development. J.
Neurosci. 24,514
-521.
Kume, T., Deng, K. Y., Winfrey, V., Gould, D. B., Walter, M. A.
and Hogan, B. L. (1998). The forkhead/winged helix gene Mf1
is disrupted in the pleiotropic mouse mutation congenital hydrocephalus.
Cell 93,985
-996.[CrossRef][Medline]
Lavdas, A. A., Grigoriou, M., Pachnis, V. and Parnavelas, J.
G. (1999). The medial ganglionic eminence gives rise to a
population of early neurons in the developing cerebral cortex. J.
Neurosci. 19,7881
-7888.
Lee, K. J., Dietrich, P. and Jessell, T. M.
(2000a). Genetic ablation reveals that the roof plate is
essential for dorsal interneuron specification. Nature
403,734
-740.[CrossRef][Medline]
Lee, S. M., Tole, S., Grove, E. and McMahon, A. P.
(2000b). A local Wnt-3a signal is required for development of the
mammalian hippocampus. Development
127,457
-467.[Abstract]
Lu, M., Grove, E. A. and Miller, R. J. (2002).
Abnormal development of the hippocampal dentate gyrus in mice lacking the
CXCR4 chemokine receptor. Proc. Natl. Acad. Sci. USA
99,7090
-7095.
Luque, J. M., Morante-Oria, J. and Fairen, A.
(2003). Localization of ApoER2, VLDLR and Dab1 in radial glia:
groundwork for a new model of reelin action during cortical development.
Brain Res. Dev. Brain Res.
140,195
-203.[CrossRef][Medline]
Luskin, M. B. and Shatz, C. J. (1985). Studies
of the earliest generated cells of the cat's visual cortex: cogeneration of
subplate and marginal zones. J. Neurosci.
5,1062
-1075.[Abstract]
Magdaleno, S., Keshvara, L. and Curran, T.
(2002). Rescue of ataxia and preplate splitting by ectopic
expression of Reelin in reeler mice. Neuron
33,573
-586.[CrossRef][Medline]
Meyer, G. and Wahle, P. (1999). The
paleocortical ventricle is the origin of reelin-expressing neurons in the
marginal zone of the foetal human neocortex. Eur. J.
Neurosci. 11,3937
-3944.[CrossRef][Medline]
Meyer, G., Soria, J. M., Martinez-Galan, J. R., Martin-Clemente,
B. and Fairen, A. (1998). Different origins and developmental
histories of transient neurons in the marginal zone of the fetal and neonatal
rat cortex. J. Comp. Neurol.
397,493
-518.[CrossRef][Medline]
Meyer, G., Goffinet, A. M. and Fairen, A.
(1999). What is a Cajal-Retzius cell? A reassessment of a
classical cell type based on recent observations in the developing neocortex.
Cereb. Cortex 9,765
-775.
Meyer, G., Perez-Garcia, C. G., Abraham, H. and Caput, D.
(2002). Expression of p73 and Reelin in the developing human
cortex. J. Neurosci. 22,4973
-4986.
Meyer, G., Cabrera Socorro, A., Perez Garcia, C. G., Martinez
Millan, L., Walker, N. and Caput, D. (2004). Developmental
roles of p73 in Cajal-Retzius cells and cortical patterning. J.
Neurosci. 24,9878
-9887.
Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S.
and Kriegstein, A. R. (2001). Neurons derived from radial
glial cells establish radial units in neocortex.
Nature 409,714
-720.[CrossRef][Medline]
Ogawa, M., Miyata, T., Nakajima, K., Yagyu, K., Seike, M.,
Ikenaka, K., Yamamoto, H. and Mikoshiba, K. (1995). The
reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule
for laminar organization of cortical neurons. Neuron
14,899
-912.[CrossRef][Medline]
Perez-Garcia, C. G., Tissir, F., Goffinet, A. M. and Meyer,
G. (2004). Reelin receptors in developing laminated brain
structures of mouse and human. Eur. J. Neurosci.
20,2827
-2832.[CrossRef][Medline]
Pinto-Lord, M. C., Evrard, P. and Caviness, V. S., Jr
(1982). Obstructed neuronal migration along radial glial fibers
in the neocortex of the reeler mouse: a Golgi-EM analysis. Brain
Res. 256,379
-393.[Medline]
Pozniak, C. D., Barnabe-Heider, F., Rymar, V. V., Lee, A. F.,
Sadikot, A. F. and Miller, F. D. (2002). p73 is required for
survival and maintenance of CNS neurons. J. Neurosci.
22,9800
-9809.
Rakic, P. (1974). Neurons in rhesus monkey
visual cortex: systematic relation between time of origin and eventual
disposition. Science
183,425
-427.
Rice, D. S. and Curran, T. (2001). Role of the
reelin signaling pathway in central nervous system development.
Annu. Rev. Neurosci. 24,1005
-1039.[CrossRef][Medline]
Rice, D. S., Sheldon, M., D'Arcangelo, G., Nakajima, K.,
Goldowitz, D. and Curran, T. (1998). Disabled-1 acts
downstream of Reelin in a signaling pathway that controls laminar organization
in the mammalian brain. Development
125,3719
-3729.[Abstract]
Ringstedt, T., Linnarsson, S., Wagner, J., Lendahl, U., Kokaia,
Z., Arenas, E., Ernfors, P. and Ibanez, C. F. (1998). BDNF
regulates reelin expression and Cajal-Retzius cell development in the cerebral
cortex. Neuron 21,305
-315.[CrossRef][Medline]
Rubenstein, J. L., Anderson, S., Shi, L., Miyashita-Lin, E.,
Bulfone, A. and Hevner, R. (1999). Genetic control of
cortical regionalization and connectivity. Cereb.
Cortex 9,524
-532.
Sheldon, M., Rice, D. S., D'Arcangelo, G., Yoneshima, H.,
Nakajima, K., Mikoshiba, K., Howell, B. W., Cooper, J. A., Goldowitz, D. and
Curran, T. (1997). Scrambler and yotari disrupt the disabled
gene and produce a reeler-like phenotype in mice.
Nature 389,730
-733.[CrossRef][Medline]
Sheppard, A. M. and Pearlman, A. L. (1997).
Abnormal reorganization of preplate neurons and their associated extracellular
matrix: an early manifestation of altered neocortical development in the
reeler mutant mouse. J. Comp. Neurol.
378,173
-179.[CrossRef][Medline]
Shimogori, T., VanSant, J., Paik, E. and Grove, E. A.
(2004). Members of the Wnt, Fz, and Frp gene families expressed
in postnatal mouse cerebral cortex. J. Comp. Neurol.
473,496
-510.[CrossRef][Medline]
Soda, T., Nakashima, R., Watanabe, D., Nakajima, K., Pastan, I.
and Nakanishi, S. (2003). Segregation and coactivation of
developing neocortical layer 1 neurons. J. Neurosci.
23,6272
-6279.
Soriano, E., Alvarado-Mallart, R. M., Dumesnil, N., Del Rio, J.
A. and Sotelo, C. (1997). Cajal-Retzius cells regulate the
radial glia phenotype in the adult and developing cerebellum and alter granule
cell migration. Neuron
18,563
-577.[CrossRef][Medline]
Soriano, P. (1999). Generalized lacZ expression
with the ROSA26 Cre reporter strain. Nat. Genet.
21, 70-71.[CrossRef][Medline]
Stewart, G. R. and Pearlman, A. L. (1987).
Fibronectin-like immunoreactivity in the developing cerebral cortex.
J. Neurosci. 7,3325
-3333.[Abstract]
Stumm, R. K., Zhou, C., Ara, T., Lazarini, F., Dubois-Dalcq, M.,
Nagasawa, T., Hollt, V. and Schulz, S. (2003). CXCR4
regulates interneuron migration in the developing neocortex. J.
Neurosci. 23,5123
-5130.
Sugitani, Y., Nakai, S., Minowa, O., Nishi, M., Jishage, K.,
Kawano, H., Mori, K., Ogawa, M. and Noda, T. (2002). Brn-1
and Brn-2 share crucial roles in the production and positioning of mouse
neocortical neurons. Genes Dev.
16,1760
-1765.
Super, H., Martinez, A. and Soriano, E. (1997).
Degeneration of Cajal-Retzius cells in the developing cerebral cortex of the
mouse after ablation of meningeal cells by 6-hydroxydopamine. Brain
Res. Dev. Brain Res. 98,15
-20.[Medline]
Super, H., Del Rio, J. A., Martinez, A., Perez-Sust, P. and
Soriano, E. (2000). Disruption of neuronal migration and
radial glia in the developing cerebral cortex following ablation of
Cajal-Retzius cells. Cereb. Cortex
10,602
-613.
Takada, S., Stark, K. L., Shea, M. J., Vassileva, G., McMahon,
J. A. and McMahon, A. P. (1994). Wnt-3a regulates somite and
tailbud formation in the mouse embryo. Genes Dev.
8, 174-189.
Takahashi, T., Goto, T., Miyama, S., Nowakowski, R. S. and
Caviness, V. S., Jr (1999). Sequence of neuron origin and
neocortical laminar fate: relation to cell cycle of origin in the developing
murine cerebral wall. J. Neurosci.
19,10357
-10371.
Takiguchi-Hayashi, K., Sekiguchi, M., Ashigaki, S., Takamatsu,
M., Hasegawa, H., Suzuki-Migishima, R., Yokoyama, M., Nakanishi, S. and
Tanabe, Y. (2004). Generation of reelin-positive marginal
zone cells from the caudomedial wall of telencephalic vesicles. J.
Neurosci. 24,2286
-2295.
Tissir, F., Wang, C. E. and Goffinet, A. M.
(2004). Expression of the chemokine receptor Cxcr4 mRNA during
mouse brain development. Brain Res. Dev. Brain Res.
149, 63-71.[CrossRef][Medline]
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J.,
Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A. and Herz, J.
(1999). Reeler/Disabled-like disruption of neuronal migration in
knockout mice lacking the VLDL receptor and ApoE receptor 2.
Cell 97,689
-701.[CrossRef][Medline]
Ware, M. L., Fox, J. W., Gonzalez, J. L., Davis, N. M., Lambert
de Rouvroit, C., Russo, C. J., Chua, S. C., Jr, Goffinet, A. M. and Walsh, C.
A. (1997). Aberrant splicing of a mouse disabled homolog,
mdab1, in the scrambler mouse. Neuron
19,239
-249.[CrossRef][Medline]
Yang, A., Walker, N., Bronson, R., Kaghad, M., Oosterwegel, M.,
Bonnin, J., Vagner, C., Bonnet, H., Dikkes, P., Sharpe, A. et al.
(2000). p73-deficient mice have neurological, pheromonal and
inflammatory defects but lack spontaneous tumours.
Nature 404,99
-103.[CrossRef][Medline]
Zhou, C. J., Zhao, C. and Pleasure, S. J.
(2004). Wnt signaling mutants have decreased dentate granule cell
production and radial glial scaffolding abnormalities. J.
Neurosci. 24,121
-126.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  A. Abellan, A. Menuet, C. Dehay, L. Medina, and S. Retaux Differential Expression of LIM-Homeodomain Factors in Cajal-Retzius Cells of Primates, Rodents, and Birds Cereb Cortex, November 18, 2009; (2009) bhp242v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Tissir, A. Ravni, Y. Achouri, D. Riethmacher, G. Meyer, and A. M. Goffinet DeltaNp73 regulates neuronal survival in vivo PNAS, September 29, 2009; 106(39): 16871 - 16876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Uchida, A. Baba, F. J. Perez-Martinez, T. Hibi, T. Miyata, J. M. Luque, K. Nakajima, and M. Hattori Downregulation of Functional Reelin Receptors in Projection Neurons Implies That Primary Reelin Action Occurs atEarly/Premigratory Stages J. Neurosci., August 26, 2009; 29(34): 10653 - 10662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Subramanian and S. Tole Mechanisms Underlying the Specification, Positional Regulation, and Function of the Cortical Hem Cereb Cortex, July 1, 2009; 19(suppl_1): i90 - i95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barber, T. Di Meglio, W. D. Andrews, L. R. Hernandez-Miranda, F. Murakami, A. Chedotal, and J. G. Parnavelas The Role of Robo3 in the Development of Cortical Interneurons Cereb Cortex, July 1, 2009; 19(suppl_1): i22 - i31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Barry, M. Piper, C. Lindwall, R. Moldrich, S. Mason, E. Little, A. Sarkar, S. Tole, R. M. Gronostajski, and L. J. Richards Specific Glial Populations Regulate Hippocampal Morphogenesis J. Neurosci., November 19, 2008; 28(47): 12328 - 12340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shibata, D. Kurokawa, H. Nakao, T. Ohmura, and S. Aizawa MicroRNA-9 Modulates Cajal-Retzius Cell Differentiation by Suppressing Foxg1 Expression in Mouse Medial Pallium J. Neurosci., October 8, 2008; 28(41): 10415 - 10421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Garcia-Moreno, L. Lopez-Mascaraque, and J. A. de Carlos Early Telencephalic Migration Topographically Converging in the Olfactory Cortex Cereb Cortex, June 1, 2008; 18(6): 1239 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Inoue, M. Ogawa, K. Mikoshiba, and J. Aruga Zic Deficiency in the Cortical Marginal Zone and Meninges Results in Cortical Lamination Defects Resembling Those in Type II Lissencephaly J. Neurosci., April 30, 2008; 28(18): 4712 - 4725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, T. Kawasaki, S. Takashima, I. Matsuda, A. Aiba, and T. Hirata Semaphorin 3F Confines Ventral Tangential Migration of Lateral Olfactory Tract Neurons onto the Telencephalon Surface J. Neurosci., April 23, 2008; 28(17): 4414 - 4422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. S. Mangale, K. E. Hirokawa, P. R. V. Satyaki, N. Gokulchandran, S. Chikbire, L. Subramanian, A. S. Shetty, B. Martynoga, J. Paul, M. V. Mai, et al. Lhx2 Selector Activity Specifies Cortical Identity and Suppresses Hippocampal Organizer Fate Science, January 18, 2008; 319(5861): 304 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kirmse, A. Dvorzhak, C. Henneberger, R. Grantyn, and S. Kirischuk Cajal Retzius cells in the mouse neocortex receive two types of pre- and postsynaptically distinct GABAergic inputs J. Physiol., December 15, 2007; 585(3): 881 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Belvindrah, D. Graus-Porta, S. Goebbels, K.-A. Nave, and U. Muller 1 Integrins in Radial Glia But Not in Migrating Neurons Are Essential for the Formation of Cell Layers in the Cerebral Cortex J. Neurosci., December 12, 2007; 27(50): 13854 - 13865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. G. Rash and E. A. Grove Patterning the Dorsal Telencephalon: A Role for Sonic Hedgehog? J. Neurosci., October 24, 2007; 27(43): 11595 - 11603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Hanashima, M. Fernandes, J. M. Hebert, and G. Fishell The Role of Foxg1 and Dorsal Midline Signaling in the Generation of Cajal-Retzius Subtypes J. Neurosci., October 10, 2007; 27(41): 11103 - 11111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakano, T. Kohno, T. Hibi, S. Kohno, A. Baba, K. Mikoshiba, K. Nakajima, and M. Hattori The Extremely Conserved C-terminal Region of Reelin Is Not Necessary for Secretion but Is Required for Efficient Activation of Downstream Signaling J. Biol. Chem., July 13, 2007; 282(28): 20544 - 20552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Paredes, G. Li, O. Berger, S. C. Baraban, and S. J. Pleasure Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains. J. Neurosci., September 13, 2006; 26(37): 9404 - 9412. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
