Dulbecco Telethon Institute at CNR-ITB, via fratelli Cervi, 93 20090 Segrate (MI), Italy
* Author for correspondence (e-mail: sbertuzzi{at}dti.telethon.it)
Accepted 8 June 2004
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SUMMARY |
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Key words: Telencephalon, Septum, MGE, Mouse
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Introduction |
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Along the DV axis, the telencephalon becomes subdivided into two large and
profoundly different territories: pallium and subpallium
(Puelles et al., 2000). The
pallium is the major source of glutamatergic neurons and it comprises the
cerebral cortex, the hippocampus and part of the septum. The subpallium is
instead the major source of GABAergic neurons and it includes the basal
ganglia, the rostral telencephalic stalk and the ventral part of the septum.
Within the basal ganglia, the lateral ganglionic eminence (LGE) will generate
the striatum; the medial ganglionic eminence (MGE) the globus pallidum, and
the preoptic area (POA) will generate oligodendrocytes and cholinergic neurons
of the basal forebrain. Originally, it was thought that cell mixing was not
possible between pallium and subpallium; however, recently, it has been
demonstrated that GABAergic interneurons are generated in the basal ganglia
and migrate across the pallium/subpallium border to populate the cerebral
cortex (Anderson et al., 1997a
;
Wichterle et al., 2001
) (for
reviews, see Marin and Rubenstein,
2001
; Marin and Rubenstein,
2003
).
In the subcortical telencephalon, several genes have been found responsible
for regionalization, cell type determination or precursor cell migration.
Among the genes important for specification, is the homeobox Nkx2.1.
Mice that lack Nkx2.1 display a ventral-to-dorsal change of fate,
with precursor cells that should generate MGE converted into LGE precursors
(Sussel et al., 1999). In the
absence of Gsh2, instead, it has been observed a loss of DV
territorialization, shown by the expansion of MGE markers, such as
Gsh1, into the LGE, and ectopic expression of pallial markers in the
dorsal LGE (Corbin et al.,
2000
; Toresson and Campbell,
2001
; Yun et al.,
2001
). Dlx genes also play a crucial role in basal telencephalon
development. These genes do not seem to be related to forebrain
regionalization, but instead are responsible for differentiation and migration
of subpallial projection neurons and interneurons that tangentially migrate to
the cerebral cortex, hippocampus and olfactory bulb
(Anderson et al., 1997a
;
Bulfone et al., 1998
;
Pleasure et al., 2000
;
Yun et al., 2002
). Moreover,
ectopic expression of Dlx genes is sufficient to induce a GABAergic phenotype
(Stuhmer et al., 2002
).
In the context of basal forebrain genetic determination, we studied
Vax1, a homeobox transcription factor expressed in the subpallium in
a pattern highly similar to that of Dlx and Gsh genes
(Anderson et al., 1999). Its
function has been studied mainly in the developing visual system
(Bertuzzi et al., 1999a
;
Hallonet et al., 1998
;
Hallonet et al., 1999
;
Ohsaki et al., 1999
;
Schulte et al., 1999
), where
it is responsible for conferring ventral identity to the optic stalk and
neural retina (S. H. Mui, J. W. Kim, G. Lemke and S.B., unpublished). Its
expression has been reported in the forebrain
(Bertuzzi et al., 1999a
;
Hallonet et al., 1998
;
Stoykova et al., 2000
), but
its function has not been studied in great detail in this territory,
especially with respect to cell migration from the ganglionic eminences.
In this paper, we study the function of Vax1 in the subcortical telencephalon. In Vax1 mutant brains, despite dorsoventral patterning occurring correctly, we have found that neurons originating from MGE and POA/AEP do not differentiate properly and accumulate in the subventricular zone (SVZ), failing to migrate into the mantle zone (MZ) efficiently. Moreover, Vax1 mutant embryos display a severe ventral midline defect, with an apparent complete morphological absence of the septal formation. As a consequence, the impaired differentiation of MGE, POA/AEP and septum leads to a loss of GABAergic neurons in the neocortex, revealing a role for Vax1 in precursor cell determination.
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Materials and methods |
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Tissue preparation and histology
Noon of the day when the vaginal plug of the pregnant dam was identified
was considered to be embryonic day (E) 0.5
(Nagy et al., 2003). Embryos
younger than E15.5 were immersion fixed in 4% paraformaldehyde (PFA). E16.5
embryos and older were anesthetized and perfused transcardially with 4% PFA in
0.1 M PBS.
RNA in situ hybridization
In situ hybridization on frozen sections was carried out using
digoxigenin-labeled probes as already described
(Tuttle et al., 1999;
Zhadanov et al., 1995
).
Immunohistochemistry
Sections were postfixed in 4% PFA for 5 minutes, rinsed in PBS and blocked
in 10% normal goat serum/0.1% Triton X-100 at room temperature for 1 hour. The
following antibodies were incubated overnight in 0.1% normal goat serum and
0.1% Triton X-100 at 4°C: monoclonal rat anti-mouse Ki67 (Dako number
M7249, 1:100); rabbit anti-Dlx (generous gift of Dr Panganiban, 1:300);
monoclonal anti-neural class IIIB-tubulin (Babco, number MM-S405-P, 1:500);
rabbit anti-calbindin D-28K (Swant number CB-38, 1:10,000). Anti-Ki67 staining
was performed after microwave epitope retrieval in 10 mmol/L citrate buffer
(pH 6). Sections were incubated for 1 hour with biotinylated secondary
antibodies: goat anti-rabbit (Jackson Immunoresearch, 1:100), goat anti-mouse
(Jackson Immunoresearch, 1:100) or donkey anti-rat (Jackson Immunoresearch
1:500). Subsequently, tissues were incubated for 30 minutes with an
avidinbiotin-peroxidase complex (Elite PK-6100, Vector Laboratories) at room
temperature, and revealed with DAB peroxidase substrate (SK-4100, Vector
Laboratories). Sections were finally dehydrated, mounted with Permount
(Fisher, number SP15-100) and photographed with an Olympus bright field
microscope (Olympus Provis AX 70) equipped with a digital camera (Nikon DXM
1200).
Birthdating analysis
Pregnant mice were injected intraperitoneally at E13.5 with a sterile
solution of bromodeoxyuridine (BrdU, Sigma) at a dose of 100 µg BrdU/g of
body weight. Newborn pups were anesthetized and perfused transcardially with
4% PFA in 0.1 M PBS. Immunohistochemistry was performed as described using a
mouse monoclonal anti-BrdU antibody (Sigma, number B2531, 1:100).
GABAergic cell counts and statistics
To obtain accurate and statistically significant counts of GABAergic cells,
we performed fluorescent immunohistochemistry using a rabbit anti-GABA
antibody (SIGMA, n° A2052, 1:1000) in an overnight incubation at 4°C,
followed by a 1 hour room temperature incubation with an anti-rabbit
FITC-conjugated secondary antibody (Jackson Immunoresearch, 1:100). Nuclei
were counterstained with DAPI (Sigma, 1:10000). Sections were subsequently
mounted on slides and photographed with a Nikon ES600 microscope equipped with
digital camera (Nikon, Coolpix 990). Three pairs of matching P0 wild type and
mutants were examined. GABA-positive cells were counted in rostral, medial and
caudal cortex within a standardized rectangular area of 200x150
µm2. Counts were performed in at least 10 slices selected at the
same level for each couple of animals. The ratio of the total number of
GABA-positive cells between mutant and wild-type cortical areas was
calculated. Ratio values were compared and represented in graphics by Excel
2000. A ratio of 1 (100%) indicates the number of GABAergic cells in the wild
type.
Organotypic slice culture experiments
Organotypic slice cultures were performed as described
(Lavdas et al., 1999;
Tobet et al., 1994
). To
examine the migratory pathways of neurons generated in septum or MGE, we
placed small crystals of 1-1'-dyoctodecyl-3-3-3'-3'
tetramethylindocarbocyanine (DiI, Molecular Probes, Eugene OR) in the region
of interest. Slices were examined under a fluorescent microscope (Nikon ES600)
after 48 hours in culture.
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Results |
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Precursor cell transition from ventricular to mantle zone
Nkx2.1 in situ hybridization and Nissl stain clearly highlight an
aberrant shape of the MGE ventricular zone. In fact, Nkx2.1 does not
show the typical contoured pattern of expression
(Fig. 2E), following the
ventricles abutting the MGE, but instead labels a large, compact mass of
darkly stained cells (Fig. 2B).
This mass of cells is located in the medial region of the basal ganglia and
has the appearance of VZ. To determine if this was correct, we examined the
expression of the LIM-homeobox gene Lhx8, which is mostly expressed
in the mantle zone of MGE and POA (Zhao et
al., 2003). As shown in Fig.
2J, although Lhx8 expression is maintained in
Vax1 mutants, it is reduced if compared with wild-type sections
(Fig. 2I).
Lhx8-positive cells accumulate in the SVZ instead of spreading into
the MZ, possibly indicating a differentiation defect. Ebf1 is a
transcription factor required for coupling neuronal differentiation with cell
cycle exit and is therefore essential for the transition of precursor cells
from the VZ to the striatal mantle
(Garcia-Dominguez et al.,
2003
; Garel et al.,
1999
). As shown in Fig.
2G,H, in Vax1-/- brains the Ebf1
expression domain is greatly reduced, with most of the cells expressing
Ebf1 confined to a small area of the LGE mantle zone, at the border
with the VZ. Although located in roughly the correct position with respect to
the lateromedial axis (suggesting again that the MGE-LGE identity has not
changed), Ebf1-positive cells seem to have failed to penetrate into
the mantle zone in an efficient way. This result, together with that obtained
with Lhx8, suggests that Vax1 mice present a defect in the
differentiation of mature neurons, from both MGE and LGE. In agreement with
this, the analysis of Ki67 at a later stage of development, E16.5
(Fig. 3D), reveals that in Vax
mutants the VZ is significantly expanded. As expected, this region is negative
for Tuj1 immunostaining, showing a labeling pattern that is complementary to
that of Ki67 (Fig. 3E,F).
Neuronal birthdating obtained by injection of BrdU at E13.5 and
immunohistochemistry at P0, reveals that neurons born at E13.5 do not disperse
into the MZ, but accumulate at the border of the VZ (arrowheads in
Fig. 3H). This area corresponds
to the developing nucleus accumbens, where Lhx8 is expressed
(Zhao et al., 2003
).
|
Dlx expression is affected in the LGE, MGE and septal area
Four Dlx genes (Dlx1, Dlx2, Dlx5 and Dlx6) are expressed
at different stages of differentiation in the subcortical telencephalon
(Anderson et al., 1997b;
Liu et al., 1997
;
Porteus et al., 1991
;
Price et al., 1991
;
Robinson et al., 1991
;
Simeone et al., 1994
). In
particular, at E13.5 Dlx1 and Dlx2 are expressed in a subset
of VZ and SVZ precursors, with a dominance of Dlx2 in the VZ.
Dlx5 is largely absent from the VZ and is almost exclusively
expressed in the SVZ and in the postmitotic mantle zone. Dlx6 instead
is mainly present in the mantle zone
(Eisenstat et al., 1999
;
Liu et al., 1997
;
Perera et al., 2004
).
Therefore, if we consider the combined expression of all of the relevant Dlx
genes we should observe the highest expression in the SVZ, a situation closely
resembling that of Vax1 expression. We analyzed the expression of Dlx
genes in Vax1 mutant mice using a pan-Dlx antibody
(Panganiban et al., 1995
). As
expected, cumulative Dlx expression is strongest in the SVZ and spans the LGE,
MGE and SA (Fig. 4A). When we
analyzed the expression of Dlx in the Vax1 mutants
(Fig. 4B), we noticed two major
defects: (1) the peaking expression in the SVZ is largely reduced throughout
the basal ganglia generating a uniform staining pattern without a defined
gradient; and (2) a significant reduction of Dlx expression in the MGE
(Fig. 4A,D). Based on the Dlx
analysis, it seems that in the absence of Vax1 the separation of VZ, SVZ and
MZ is partly lost, generating a rather flat gradient of Dlx expression,
compared with the sharp one present in the wild type. Interestingly, although
Vax1 and Dlx present a wide overlapping expression throughout the
subcortical telencephalon, Dlx expression is mostly affected in the MGE
(Fig. 4D). We hypothesized that
this could be due to a specific interaction occurring between a Dlx gene and
Vax1 in the MGE via a MGE-specific regulator. For this reason, we
checked the Gsh1 transcription factor, which is mainly expressed in
the MGE and only minimally in the LGE
(Corbin et al., 2003
;
Toresson and Campbell, 2001
;
Valerius et al., 1995
;
Yun et al., 2003
). In
Fig. 4G,H we show that in
Vax1-/- mutants Gsh1 expression is almost
completely absent (at E13.5 its signal is minimal, slightly above noise
levels, while at E16.5 is completely absent, data not shown), consistent with
the possibility of a genetic cascade controlled by Vax1, regulating
both Dlx and Gsh1.
|
|
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One alternative hypothesis that could be considered is that Vax1 mutants present a delay in GABAergic cell migration from the subcortical telencephalon to the cortex. Unfortunately, 94% of Vax1 mutants die at birth, and only 6% survive to P20. Given the small number of viable P20 Vax1 mutants, it was impossible to perform thorough statistics, as we did at P0. However, we performed GABA cell counts at P20 in a single mutant brain, confirming the P0 defect, a finding that probably rules out the possibility of a delayed migration of GABAergic precursor cells.
Earlier studies provided evidence in support of the hypothesis that loss of
inhibitory GABAergic neurons determines neuronal hyperexcitability in cortex,
eventually leading to seizures (Ribak et
al., 1982; Ribak et al.,
1979
). More recent investigations using animal models have
confirmed that impairment of GABAergic neurotransmission is implicated in
epilepsy (DeLorey et al.,
1998
; Powell et al.,
2003
; Treiman,
2001
), and provided genetic evidence that the GABAA
receptor is directly involved in human idiopathic epilepsy
(Baulac et al., 2001
;
Treiman, 2001
). Indeed, during
routine handling of Vax1-mutant mice we have observed spontaneous
convulsions, resembling clonic seizures, possibly indicating that the loss of
GABAergic neurons in these mice has severe consequences on cortical
physiology.
In summary, we have shown that P0 mutants have a decreased number of cortical GABAergic interneurons; however, the MGE defective differentiation does not seem to be severe enough to explain the 30% to 44% reduction in GABAergic interneurons. One reasonable possibility to explain this discrepancy would be cell loss by apoptosis, but we were unable to detect significantly altered levels of cell death by TUNEL staining (data not shown). Other work (J. M. Soria and A. Fairén, personal communication) has found that the septum significantly contributes to cortical GABAergic interneurons. For this reason, we turned our attention to the septum of Vax1-/- mutants.
The septal area is absent in Vax1-/- mice
The septum is part of the limbic system and is a telencephalic structure
located under the corpus callosum, above the anterior commissure and between
the medial walls of the lateral ventricles. Soria and Fairén describe a
migratory stream of cells moving subpially from the septum to the neocortex
and including both presumptive Cajal-Retzius cells and also interneurons
(personal communication). Vax1 mutants do not form the septum,
presenting a midline fusion of the ventral forebrain
(Bertuzzi et al., 1999b;
Hallonet et al., 1999
),
therefore this structure is completely absent at E 16.5
(Fig. 7A,B;
Fig. 4C,D)
(Hallonet et al., 1999
). Owing
to the lack of septum formation, (broken line in
Fig. 7A,B) instead of showing
the normal contoured appearance the lateral ventricles are fused together
forming a single U-shaped holoprosencephalic ventricle. We will describe the
generation of the septal defect in detail in the future; here, we address the
consequences of the fact that the septal midline region is occupied by the
large, compact mass of undifferentiated cells, which cannot differentiate and
migrate correctly (Fig. 7). We
wanted to verify that the GABAergic cell migration from the septum was indeed
missing in the Vax1-/- brains. We cultured E13.5 brains
from wild-type and Vax1 mutants in an organotypic culture assay
(Tobet et al., 1994
),
implanting in the developing septal area a small piece of bamboo soaked in the
fluorescent tracer DiI. Fig.
7C-H shows that whereas an abundant stream of migratory cells has
taken the lateral pathway of migration toward the pallium in wild-type brains,
there is no sign of migration from the Vax1 mutants. This result
helps significantly in explaining the loss of cortical GABAergic cells, which
could not be taken into account only by the partial loss of differentiation of
MGE precursor cells.
|
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Discussion |
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Evidence that in Vax1-/- mice reduced migration from the basal ganglia and absent migration from the septum cause a severe GABAergic cell depletion in cortex
An important feature of CNS development is that pools of multipotent
precursor cells proliferate in the neuroepithelium, close to the ventricles,
and migrate to their final location becoming part of highly organized
circuits. Within the telencephalon, the key process of radial migration
provides neurons to the cortex
(Marin-Padilla, 1971;
Rakic, 1974
). The existence of
tangentially oriented cells in the cerebral cortex has been recognized for a
long time, but only recently it has been proven that the process of tangential
migration from the subcortical telencephalon contributes to GABAergic
interneurons of the dorsal pallium (for reviews, see
Marin and Rubenstein, 2001
;
Marin and Rubenstein, 2003
).
Information obtained from several mouse mutants (see Results section) has
demonstrated that the vast majority of GABAergic interneurons that modulate
the function of glutamatergic pyramidal cells originate from precursor cells
located in the MGE and POA/AEP. In this work, we wanted to study whether the
loss of expression of Vax1 in the VZ and SVZ of the subcortical
telencephalon impaired tangential migration. We have found that migrating
cells from the MGE, labeled with calbindin and Lhx8, in part tend to
accumulate at the border of the SVZ without reaching their final destination.
We propose that this defect could be mediated by Dlx genes. In support of this
hypothesis, we have observed a partial loss of Dlx proteins in the MGE.
Moreover, Dlx1/2 mutants show a similar defect, in that cells
differentiate abnormally and do not leave the SVZ efficiently
(Anderson et al., 1997b
). We
have carefully estimated the GABAergic cell loss in Vax1 mutants in
the range between 30% and 44%, depending on the rostrocaudal levels
considered. As the reduction of migration from the MGE was rather mild, and
migratory cells have also been identified from the mutant POA in matrigel cell
cultures, it was not possible to explain such a severe loss of GABAergic cells
in cortex. For this reason, we turned our attention to the septum, which we
knew was completely missing in Vax1 mutants. Soria and Fairén
(personal communication) have found that the septal area is a source of
GABAergic interneurons that are Arx, PSANCAM and calbindin positive, which
migrate subpially to the neocortex. The stream of cells labeled by DiI placed
in the septal area at E13.5 is conspicuous in the wild type and completely
absent in Vax1 mutants (Fig.
7G,H). Indeed, the complete loss of septal GABAergic interneurons
and the partial reduction of the MGE and POA/AEP pools, can account for the
numbers of total GABAergic cell loss. Unfortunately, the number of cells
labeled with DiI is highly dependent on the quantity and precise location of
dye application, making quantitative comparisons between different samples
difficult using this method. However, a rough estimate suggests that the loss
of cortical GABAergic cells can be explained by the basal ganglia and septum
defects combined.
We find it interesting that the conspicuous cortical GABAergic cell loss in Vax1-/- mutants could be the cause, at a physiological level, of the spontaneous and induced convulsions that resemble clonic seizures, which we have observed in the few surviving P20 mutant mice.
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ACKNOWLEDGMENTS |
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