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The Journal of Neuroscience, January 1, 2003, 23(1):167-174
Identification of Two Distinct Progenitor Populations
in the Lateral Ganglionic Eminence: Implications for Striatal and
Olfactory Bulb Neurogenesis
Jan
Stenman1, 2,
Håkan
Toresson2, and
Kenneth
Campbell1
1 Division of Developmental Biology, Children's
Hospital Research Foundation, Cincinnati, Ohio 45229-3039, and
2 Wallenberg Neuroscience Center, Division of Neurobiology,
Lund University, S-221 84 Lund, Sweden
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ABSTRACT |
The lateral ganglionic eminence (LGE) is known to give rise to
striatal projection neurons as well as interneurons, which migrate in
the rostral migratory stream (RMS) to populate the granule cell and
glomerular layers of the olfactory bulb. Because all of these neuronal
subtypes express Distalless-related (DLX) homeobox proteins
during their differentiation, we set out to further characterize
progenitors in the Dlx-positive domain of the LGE.
Previous studies have shown that the LIM homeobox protein Islet1
(ISL1) marks the LGE subventricular zone (SVZ) and differentiating striatal projection neurons. However, ISL1 is not expressed in neurons
of the developing olfactory bulb or the RMS. We show here that the
dorsal-most portion of the Dlx-expressing region of the LGE SVZ lacks ISL1 cells. This dorsal domain, however, contains cells
that express the ETS transcription factor Er81, which is also
expressed in granule and periglomerular cells of the developing and
adult olfactory bulb. Moreover, the adult SVZ and RMS contain numerous
Er81-positive cells. Fate-mapping studies using
Dlx5/6-cre transgenic mice demonstrate that
Er81-positive cells in the granule cell and glomerular layers of the
olfactory bulb derive from the Dlx-expressing SVZ
region. These findings suggest that the LGE SVZ contains two distinct
progenitor populations: a
DLX+;ISL1+ population
representing striatal progenitors and a
DLX+;Er81+ population comprising
olfactory bulb interneuron progenitors. In support of this, mice mutant
for the homeobox genes Gsh2 and Gsh1/2,
which show olfactory bulb defects, exhibit dramatically reduced numbers
of Er81-positive cells in the LGE SVZ as well as in the olfactory bulb mantle.
Key words:
DLX; Er81; Gsh1; Gsh2; Islet1; NKX2.1; Small eye; telencephalon
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Introduction |
The extensive neuronal diversity of
the mature nervous system is central to its many complex functions.
Recent studies have begun to uncover some of the mechanisms that
regulate the generation of this diversity during nervous system
development. At spinal cord levels, distinct neuronal subtypes have
been shown to arise from discrete progenitor domains positioned along
the dorsoventral axis (Jessell, 2000 ). Combinatorial codes of
transcription factors define these progenitor domains and appear to
regulate the development of specific neuronal populations, such as
motor neurons versus interneurons (Briscoe et al., 2000). Similar
progenitor domains have not, as yet, been well defined in the anterior
regions of the developing brain.
Recent studies have shown that both radial and tangential migration
contributes significantly to neuronal diversity within distinct
telencephalic regions (for review, see Marin and Rubenstein, 2001).
Whereas projection neurons seem to be generated from the germinal zones
directly adjacent to the telencephalic structure they ultimately
populate, interneurons appear to be produced in restricted regions and
undergo extensive migration to reside in different telencephalic
regions. An example of this occurs in the medial ganglionic eminence
(MGE), where a number of distinct interneuronal populations are
generated and subsequently migrate tangentially to populate distant
telencephalic regions, such as the striatum, cortex, and hippocampus
(Lavdas et al., 1999; Pleasure et al., 2000; Wichterle et al., 1999,
2001; Anderson et al., 2001). Another example is in the lateral
ganglionic eminence (LGE), which has been shown to give rise to
striatal projection neurons (Deacon et al., 1994; Olsson et al., 1995,
1997, 1998; Wichterle et al., 2001) as well as interneurons that
migrate in the rostral migratory stream (RMS) and populate both the
glomerular and granule cell layers of the olfactory bulb (Wichterle et
al., 1999, 2001). That both striatal projection neurons and olfactory
bulb interneurons are derived from the LGE is consistent with data from
Mash1 and Dlx1/2 homozygous mutants (Anderson et
al., 1997; Bulfone et al., 1998; Casarosa et al., 1999). Both of these
genes are expressed in cells of the ventricular zone (VZ) and/or
subventricular zone (SVZ) of the LGE, and the loss-of-function mutants
show differentiation defects in both the striatum and the olfactory
bulb. Moreover, in Gsh2 mutants, which have reduced
Mash1 and Dlx gene expression in the LGE, leaving
their expression in the MGE relatively unaffected, both striatal and
olfactory bulb defects are observed (Corbin et al., 2000; Toresson et
al., 2000; Toresson and Campbell, 2001; Yun et al., 2001). Distinct
subtypes of cortical and hippocampal interneurons have also been
suggested to arise from the LGE at later stages of neurogenesis
(Pleasure et al., 2000; Anderson et al., 2001).
It remains unclear whether all of these LGE-derived neuronal subtypes
are generated from a common progenitor or whether distinct progenitor
pools exist in the LGE, as is the case in the spinal cord. We provide
evidence here that at least two distinct progenitor pools exist in the
LGE, and suggest that they contribute differentially to striatal and
olfactory bulb neurogenesis.
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Materials and Methods |
Animals: Generation of Dlx5/6-cre-IRES-EGFP
mice. cre recombinase cDNA was subcloned
into the pIRES2EGFP vector (Clontech, Palo Alto, CA).
cre-internal ribosome entry site
(IRES)-enhanced green fluorescent protein
(EGFP) was subsequently subcloned into a vector containing
the mouse id6/id5 enhancer (Zerucha et al., 2000) provided
by Dr. M. Ekker (University of Ottawa, Ottawa, Canada).
Pronuclear injections of the Dlx5/6-cre-IRES-EGFP construct were performed by the transgenic core at Children's Hospital Research Foundation. Founders were identified by PCR using the following primers: GFP5, CTA ACG TTA CTG GCC GAA; GFP3, ACT TGA AGA AGT CGT GCT.
Three independent lines were established, and all show similar
expression of the transgene. The Dlx5/6-cre-IRES-EGFP mice
were kept on a C57BL/6 background. Heterozygote embryos and postnatal
day 0 (P0) pups were obtained from heterozygote and wild-type crosses
and typed by visual inspection for enhanced green fluorescent protein
(EGFP) under a fluorescent microscope. Adult
Dlx5/6-cre-IRES-EGFP/gtROSA double transgenic brains were obtained by crossing heterozygous
B6;129-Gtrosa26tm1Sho
(gtROSA) mice (Mao et al., 1999) (obtained from The
Jackson Laboratory, Bar Harbor, ME) with hemizygous
Dlx5/6-cre-IRES-EGFP mice.
Gsh1 (Li et al., 1996), Gsh2 (Szucsik et al.,
1997), and Small eye (Sey) mice and embryos were
typed as described previously (Toresson et al., 2000; Toresson and
Campbell, 2001). gtROSA mice were genotyped as described in
the Gtrosa26 genotyping protocol of The Jackson Laboratory
(http://www.jax.org). For staging of embryos, the morning of vaginal
plug was designated as embryonic day 0.5 (E0.5).
Immunohistochemistry. Embryos and P0 pups were processed as
described previously (Toresson et al., 2000). Adult brains were removed fresh, immersion fixed in 4% paraformaldehyde in PBS
overnight at 4°C, and then placed in PBS with 30% sucrose for
at least 72 hr at 4°C before sectioning on a cryostat. The adult
brains were either sectioned at 30-40 µm and kept as free-floating
in PBS or sectioned at 8 µm and mounted directly onto slides.
Immunohistochemistry was performed on the slide-mounted sections as
described previously (Olsson et al., 1997), with the modification that
only 0.3% H2O2 was used
for 10-15 min instead of 3%
H2O2. The 30- to
40-µm-thick adult brain sections were immunostained free-floating and
subsequently mounted onto slides. Primary antibodies were used at the
following concentrations: rabbit anti-Distalless (i.e., DLX) (1:1000;
provided by G. Panganiban, University of Wisconsin-Madison, Madison,
WI), rabbit anti-Er81 (1:5000; provided by S. Morton and T. Jessell, Columbia University, New York, NY), chicken anti-GFP
(1:5000; Chemicon, Temecula, CA), rabbit anti-Islet1/2 (ISL1/2) (1:500; provided by T. Edlund, Umeå University, Umeå,
Sweden), and goat anti-NKX2.1 (1:1200, Santa Cruz Biotechnology,
Santa Cruz, CA). For fluorescent staining, donkey anti-rabbit
antibodies conjugated to Cy3 (Jackson ImmunoResearch, West Grove, PA)
or donkey anti-chicken antibodies conjugated to FITC (Jackson
ImmunoResearch) were used as secondary antibodies (Jackson
ImmunoResearch). NKX2.1 was visualized using biotinylated horse
anti-goat antibodies (Vector Laboratories, Burlingame, CA) and
streptavidin conjugated with FITC for fluorescent detection (Jackson
ImmunoResearch). Confocal microscopy was performed using a Zeiss
(Thornwood, NY) LSM510 confocal microscope. For bright-field staining,
biotinylated swine anti-rabbit antibodies (Dako, Carpinteria, CA) were
used with the ABC kit (Vector Laboratories) and diaminobenzidine
(Sigma, St. Louis, MO) as the final chromogen.
5-bromo-4-chloro-3-indolyl- -D-galactopyranoside
histochemistry.
5- bro-mo-4-chloro-3-indolyl--D-galactopyranoside
(X-gal) staining was performed on both slide-mounted and free-floating sections. First, they were washed in 0.02% NP-40 and 2 mM MgCl2 in PBS. They were
then incubated in the staining solution (5 mM K3Fe(CN)6, 5 mM
K4Fe(CN)6, 2 mM MgCl2, 0.01%
deoxycholate, 0.02% NP-40, and 1 mg/ml X-gal) at 37°C until the
stain was clearly visible. The sections or slides were then transferred
to a potassium PBS solution and processed for
immunohistochemistry as described above.
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Results |
ISL1 overlaps extensively with the Dlx5/6-expressing
domain of the LGE
The LGE is known to give rise to striatal projection neurons as
well as interneurons populating the olfactory bulb (Deacon et al.,
1994; Olsson et al., 1997, 1998; Wichterle et al., 2001). However, it
is not clear whether these neurons are generated from a common
progenitor cell in the SVZ of the LGE or from distinct progenitor
pools. Because both striatal projection neurons and olfactory bulb
interneurons express DLX proteins during their differentiation, we set
out to further characterize progenitors in the Dlx-positive
domain of the LGE.
To aid in this analysis, we made transgenic mice expressing cre
recombinase and EGFP from a bicistronic construct under
the control of the Dlx5/6 enhancer element
id6/id5 (Zerucha et al., 2000). At E12.5, DLX proteins,
including DLX1, DLX2, DLX5, and DLX6 (recognized by an antibody against
Drosophila Distalless) (Panganiban et al., 1995) are
expressed throughout the MGE and the LGE, including both the VZ and the
SVZ (Fig. 1A). EGFP
expression from the Dlx5/6 enhancer is confined to the SVZ
and forming mantle (Fig. 1B), and merged confocal
images show that EGFP-expressing cells constitute a subdomain of the
DLX-positive domain (Fig. 1C). This is in accordance with
the expression of lacZ from the Dlx5/6 enhancer
(Zerucha et al., 2000; Stuhmer et al., 2002) as well as the expression
of the endogenous Dlx5 and Dlx6 genes (Liu et
al., 1997). At E16.5, DLX proteins are again found in the VZ, SVZ, and
mantle regions (Fig.
2A). However, the
Dlx5/6-driven EGFP is confined to the SVZ and mantle (Fig.
2B,C), closely resembling the endogenous
Dlx5/6 expression pattern.
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Figure 1.
Expression of DLX (A),
ISL1 (D), Er81 (G, J), and
EGFP expressed from the Dlx5/6 element (B, E,
H) at E12.5. A, DLX proteins are
expressed in cells of the VZ and SVZ of the LGE, whereas the
EGFP-expressing cells are predominantly localized to the SVZ (B,
C). D, ISL1 expression is found in the SVZ and
overlaps extensively with EGFP expression (E, F).
Note, however, the lack of ISL1 in the dorsal-most portion of the
EGFP-expressing domain (asterisk in D and
F). In the dorsal portion of the LGE,
Er81-positive cells (G) overlap with the dorsal
Dlx5/6-driven EGFP expression (H,
I). The arrow in G and
I points to the Er81-positive cell cluster in the DLX
domain. At more anterior regions, Er81 expression is seen in the
olfactory bulb primordium (J). Note that at this
stage EGFP (i.e., Dlx5/6) expression is not
detected at the anterior level (K, L).
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Figure 2.
Expression of DLX (A),
ISL1 (D), Er81 (G), and
EGFP expressed from the Dlx5/6 element (B, E,
H) at E16.5. Extensive overlap of DLX
(A) and EGFP (B, C) is seen in the
SVZ of the LGE. As was the case at E12.5, the VZ expression of DLX
proteins is not overlapping with EGFP (C). ISL1
(D) and EGFP (E) also show
significant overlap in the LGE SVZ (F). Note
again the lack of ISL1 expression in the dorsal EGFP domain
(asterisk in D and
F). Again, the dorsal LGE contains
Er81-expressing cells (arrow in G), which
overlap with EGFP expression (arrow in
I). Er81 is also found in scattered cells of the
striatum and in the ventrolateral VZ of the pallium
(G). Double-staining with Er81
(red) and NKX2.1 (green)
(J-L) reveals coexpressing cells in the remnant
of the MGE (K) and in the globus pallidus
(GP) as well as in scattered striatal neurons
(L).
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Previous studies have demonstrated that the LIM homeobox protein
ISL1 is expressed in differentiating striatal neurons, including the
projection neurons and cholinergic interneurons (Toresson et al., 2000;
Toresson and Campbell, 2001; Wang and Liu, 2001). The ISL1-expressing
cells in the SVZ of the LGE (Figs. 1D,
2D) and in the developing striatum (Fig.
2D) overlap extensively with the domain expressing
EGFP from the Dlx5/6 enhancer (Figs. 1F, 2F). However, in the dorsal-most portion of the LGE,
an EGFP-positive (i.e., DLX+) and
ISL1-negative domain is evident both at E12.5 (Fig.
1F) and at E16.5 (Fig. 2F). Thus
already at E12.5, two separate SVZ progenitor pools can be identified
in the Dlx5/6-expressing domain of the LGE: one defined by
the expression of ISL1
(DLX+;ISL1+)
and another by its absence
(DLX+;ISL1 ).
The overlap in the SVZ expression of Dlx5/6-driven EGFP and ISL1 is greatly reduced at P0 (Fig.
3A). This is in accordance with the time course of striatal neurogenesis, which ends around birth
(Bayer and Altman, 1995). As mentioned above, olfactory bulb
interneurons in both the granule cell and periglomerular layers are
also derived from the Dlx5/6-expressing LGE SVZ (Fig. 3B); however, at no stage examined have we observed
ISL1-positive olfactory bulb neurons (Fig. 3B) (data not
shown). Thus the
DLX+;ISL1+
domain in the LGE SVZ may contain progenitors that are restricted to
striatal neuron fates.
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Figure 3.
Expression of ISL1 (A, B), Er81
(C-E), and EGFP expressed from the
Dlx5/6 element (A-E) at P0. At
birth, few ISL1-positive cells remain in the EGFP-expressing SVZ region
(A). Furthermore, no ISL1 cells are detected in
the newborn olfactory bulb, which contains many differentiating neurons
positive for Dlx5/6-driven EGFP
(B). Unlike ISL1, Er81 is found coexpressed
with many EGFP cells of the SVZ (C)
as well as in many neurons of the olfactory bulb (D, E).
E, High power of the outer mantle layer of the olfactory
bulb (box in D) showing presumptive
periglomerular neurons coexpressing Er81 and EGFP. GCL,
Granule cell layer; GL, glomerular layer;
lv, lateral ventricle.
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Er81 marks a subdomain of the
Dlx5/6-expressing LGE
To further characterize the
DLX+;ISL1
domain of the LGE SVZ, we looked for markers expressed in this region.
A recent study by Yun et al. (2001) demonstrated that the ETS
transcription factor gene Er81 is expressed in the
dorsal-most portion of the LGE VZ. Although the protein expression of
Er81 is not detected at high levels in the LGE VZ, we observed that at
both E12.5 (Fig. 1G-I) and E16.5 (Fig.
2G-I), Er81 is expressed in the
DLX+;ISL1
domain of the SVZ, which presumably lies directly under the region of
the LGE VZ expressing the Er81 gene (Yun et al., 2001). This expression domain is most evident at rostral levels of the LGE. After
birth (i.e., P0), many cells in the postnatal SVZ still coexpress EGFP
from the Dlx5/6 enhancer and Er81 (Fig. 3C).
The expression of Er81 is by no means specific to the
DLX+;ISL1
SVZ domain. It is also expressed in the VZ of the ventrolateral pallium
(i.e., cortical VZ) (Fig. 2G), in the medial portion of the
MGE, in the differentiating pallidum (including the globus pallidus)
(Fig. 2J), as well as in scattered cells of the
developing striatum (Fig. 2G). The scattered expression of
Er81 in the developing striatum suggests that this transcription factor
may mark striatal interneurons or a subpopulation thereof. Although it
is possible that these cells could originate from the
DLX+;Er81+
domain of the LGE SVZ, it is more likely that they originate from the
adjacent MGE. Indeed, most striatal interneurons have been shown to
derive from the MGE and subsequently migrate laterally into the
developing striatum (Olsson et al., 1998; Sussell et al., 1999; Marin
et al., 2000). Interneurons in the striatum are known to express the
MGE-specific homeobox transcription factor NKX2.1 (Sussell et al.,
1999; Marin et al., 2000). Indeed, the majority of Er81-expressing
cells in the striatum also express NKX2.1 (Fig. 2L),
indicating that they are likely derived from the MGE and represent
striatal interneurons. Moreover, a stream of Er81/NKX2.1-coexpressing
cells can be seen oriented in the direction of the striatum (Fig.
2J,K), suggestive of the migratory path these
cells may take.
In addition to the
DLX+;Er81+
region in the LGE SVZ, Er81 is also found in the rostrally located
DLX primordia of the olfactory bulb at
E12.5 (Fig. 1J-L). Expression of Er81 is maintained
in the germinal zone of the olfactory bulb at later stages as well as
in cells of the mantle region (Fig. 3D). Interestingly, EGFP
driven from the Dlx5/6 enhancer is found in cells of the
developing olfactory bulb by E16.5, both in the germinal zone as well
as in the developing granule and periglomerular cells (data not shown).
Many of the EGFP-expressing cells in the P0 olfactory bulb were found
to coexpress Er81, especially in the developing glomerular layer (Fig.
3D,E). These findings suggest that cells in the
DLX+;Er81+
region of the LGE SVZ could represent olfactory bulb interneuron progenitors.
Er81 in the adult SVZ and olfactory bulb
Neurogenesis in the olfactory bulb is known to continue throughout
the postnatal period and into adulthood (Luskin, 1993; Lois and
Alvarez-Buylla, 1994; Bayer and Altman, 1995). At present, the
relationship between the LGE and the postnatal/adult SVZ is not clear;
however, the postnatal/adult SVZ comes to reside on the ventricular
wall of the striatum (the principal derivative of the LGE). Moreover,
cells in the postnatal/adult SVZ express DLX proteins (Fig.
4A), suggestive of an
LGE origin. Er81 is also detected in cells of the postnatal/adult SVZ
(Fig. 4B). Furthermore, Er81 can be detected in cells
of the RMS and in olfactory bulb neurons, in the granule cell layer,
and in the glomerular layer (Fig. 4C,D). In the granule cell
layer, Er81 expression is strongest in the outer regions and is also
found in the granule cells of the mitral layer (Fig.
4D).
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Figure 4.
DLX and Er81 expression in the adult SVZ, RMS,and
olfactory bulb. A, Although DLX proteins are not
expressed in the adult striatum, many cells express DLX in the SVZ
(high-power inset). B, Er81-positive
cells are also found in the SVZ (high-power inset) as well as in the
RMS (C, D). In the olfactory bulb, Er81 expression is
observed in periglomerular cells and in granule cells of the mitral
layer and outer portions of the granule cell layer. Note that Er81 is
also observed in scattered striatal and nucleus accumbens neurons as
well as in deep layers of the cerebral cortex. ac,
Anterior commissure; cc, corpus callosum;
EPL, external plexiform layer; GCL,
granule cell layer; GL, glomerular layer;
ML, mitral layer; N Acc, nucleus
accumbens.
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As suggested by the embryonic analysis, the
DLX+;Er81+
region may give rise to olfactory bulb interneurons. To address this issue, we crossed Dlx5/6-cre-IRES-EGFP mice with
gtROSA reporter mice (Mao et al., 1999), which have a
floxed "stop transcription" sequence in front of the
lacZ gene. In cells in which cre recombinase is
expressed, the "stop" sequence is recombined out and the
lacZ is expressed. In this case, all cells that express or
expressed the Dlx5/6 enhancer at some point will express
-galactosidase from the lacZ gene. The striatum, which is
known to be derived from the LGE (Olsson et al., 1997; Wichterle et
al., 2001), shows many X-gal-positive cells (Fig.
5A). Because the X-gal
reaction product is only a small dot located in the cytoplasm of
the positive cell, we used thin (i.e., 8 µm) sections to colocalize
the X-gal in subtypes of striatal and olfactory bulb neurons. In thin
sections, the overwhelming majority of striatal neurons expressing
dopamine and cAMP-regulated phosphoprotein (DARPP)-32, a
marker of striatal projection neurons (Anderson and Reiner, 1991),
coexpressed the X-gal reaction product (Fig. 5B). In
addition to the X-gal staining of striatal neurons, many cells were
X-gal-positive in the granule cell and glomerular layers of the
olfactory bulb (Fig. 5C). Analysis of thin sections showed
that the majority of Er81-positive cells in the glomerular (Fig.
5D) and granule cell layers double-stain for X-gal (Fig.
5E). Moreover, the granule cells of the mitral layer
coexpress Er81 and X-gal. These findings support the notion that
periglomerular and at least a portion of the granule cells originate
from the DLX+;
Er81+ LGE domain.
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Figure 5.
Fate mapping of Dlx5/6-expressing
cells. In thick sections (i.e., 30-40 µm) from mice double
transgenic for Dlx5/6-cre and gtROSA,
many X-gal-positive cells (blue dots) are found in the
adult striatum and septal regions (A). In thin
sections (i.e., 8 µm), most DARPP-32-expressing cells in the striatum
are found to be X-gal-positive (B).
C, A stream of X-gal positive cells is seen exiting the
RMS at olfactory bulb levels and labeling the granule cell layer (GCL)
and glomerular layer (GL) in thick sections. In thin sections, nearly
all Er81-positive periglomerular cells stain with X-gal
(D), as was the case for Er81-expressing granule
cells in the mitral layer (extreme left in
E), and in the outer granule cell layers
(E). ac, Anterior commissure;
cc, corpus callosum.
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Genetic regulation of the
DLX+;Er81+ LGE domain
Recent studies (Corbin et al., 2000; Stoykova et al., 2000;
Toresson et al., 2000; Yun et al., 2001) have demonstrated that the developmental regulators Pax6 and
Gsh2 are required for the maintenance of dorsoventral
identity and, in particular, for the correct formation of the boundary
between the pallium (i.e., developing cortex) and the LGE. In
Gsh2 homozygotes, the expression of Mash1 and
Dlx genes is lost from most of the progenitors in the LGE; in their place, the dorsal regulators Pax6,
Neurogenin1 (Ngn1) and Ngn2 are
expanded ventrally. The converse is the case in the Sey
homozygotes (i.e., Pax6 mutants). We were interested in
examining the
DLX+;Er81+
domain of the LGE SVZ in Gsh2 and Pax6 mutants.
In the Gsh2 mutant at E18.5, the ISL1 domain is decreased in
size, as described previously (Toresson et al., 2000; Toresson and
Campbell, 2001). Interestingly however, ISL1-positive cells occupy the
dorsal-most portion of the mutant LGE (Fig.
6B), unlike in the wild
type (Fig. 6A). The reduction in ISL-positive cells
in the LGE of Gsh1/2 double homozygous mutants is even more
severe than that in the single Gsh2 mutants (Toresson and
Campbell, 2001); however, as in the Gsh2 mutants, ISL1 cells
occupy the dorsal-most domain of the LGE (Fig. 6C). Er81
staining in the LGE SVZ shows a decreased number of cells, occupying a significantly smaller domain, in the Gsh2 (Fig.
6E) and Gsh1/2 mutants (Fig.
6F) compared with wild types (Fig.
6D). Hence, the
DLX+;Er81+
domain of the LGE SVZ appears to be severely depleted in Gsh mutants.
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Figure 6.
A-I, Altered expression of ISL1
and Er81 in Gsh and Sey homozygous
mutants. ISL1 (A-C) and Er81
(D-I) expression in E18.5 wild-type (A,
D, G), Gsh2 (B, E, H), and
Gsh1/2 (C, F, I) mutants is shown.
A, ISL1 expression is excluded from the dorsal-most
portion of the wild-type LGE (asterisk). In
Gsh2 (B) and Gsh1/2
(C) mutants, ISL1-positive cells are found in the
dorsal LGE region. Open arrowheads in
A-C point to the LGE/cortex angle. D,
Er81-positive cells are found in the dorsal (i.e., ISL1-negative;
marked by an asterisk) LGE region of wild types. In
Gsh2 (E) and Gsh1/2
(F) mutants, few Er81-expressing cells are
observed in the dorsal-most LGE (arrows in
E). G, Er81-positive cells are found
in periventricular regions as well is in the outer mantle regions
of the olfactory bulb, presumably in the differentiating
periglomerular cells. Although the periventricular Er81 staining
remains in Gsh2 (H) and
Gsh1/2 (I) mutants,
Er81-expressing cells in the olfactory bulb mantle are severely reduced
in these mutants. J, K, Altered expression of Er81
expression in the Sey/Sey telencephalon.
J, Er81-positive cells are present in the LGE SVZ
(arrows) and in the VZ of the ventrolateral pallium of
the E14.5 wild type. K, In Sey/Sey
mutants at E14.5, pallial VZ expression is lost; however, SVZ
expression expands into the dorsal telencephalon. GCL,
Granule cell layer; GL, glomerular layer;
KO, knockout.
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If our conjecture that the
DLX+;Er81+
domain of the LGE SVZ gives rise to olfactory bulb interneurons is
correct, then there should be fewer Er81-positive neurons in the
olfactory bulbs of Gsh2 and Gsh1/2 mutants.
Indeed this seems to be the case. In Gsh2 mutants, only
scattered cells expressing Er81 can be detected in the mantle of the
olfactory bulb (Fig. 6H), whereas the
Gsh1/2 mutants show an even more severe reduction (Fig.
6I). Despite the reduced staining in the mantle
regions of the Gsh mutant olfactory bulbs, Er81 remains
expressed in periventricular regions of the mutant olfactory bulb. As
described above, at E12.5, a
DLX;Er81+
domain is found at rostral levels in the primordia of the olfactory bulb. Thus it is possible that progenitors of the locally derived neurons (i.e., the projection neurons) also express this marker and
downregulate it with differentiation.
Yun et al. (2001) have previously analyzed Er81 gene
expression in Sey/Sey (i.e., Pax6)
mutants. They showed that the expression of Er81 expands
dorsally, similar to the other ventral regulators (e.g.,
Mash1, Gsh2, and Dlx genes). Our data
are in agreement with this, however: because the Er81 protein
expression is confined to the SVZ of the LGE, we observed an
interesting change in its expression pattern within the developing
cortex. In wild types at E14.5, Er81 is also expressed in the
ventrolateral VZ of the pallium (Fig. 6J) (see also
Fig. 2G, E16.5). Although the SVZ expression of Er81 is
expanded dorsally in Sey/Sey mutants at this stage, it
appears to be at the expense of its normal expression in the pallial VZ
(Fig. 6K). However, this is in accordance with the
dorsal shift of other ventral markers such as Gsh2,
Mash1, and Dlx genes (Stoykova et al., 2000,
Toresson et al., 2000; Yun et al., 2001). Unfortunately, in
Sey/Sey mutants the olfactory bulb does not form correctly
(Anchan et al., 1997; Jimenez et al., 2000), so it is difficult to
determine whether they would have altered numbers of interneurons.
| |
Discussion |
The results of this study demonstrate the existence of two
distinct progenitor populations in the SVZ of the LGE. These progenitor pools subdivide the Dlx-expressing region of the LGE into a
DLX+;ISL1+
domain that occupies most of the LGE SVZ and a
DLX+;Er81+
domain in the dorsal-most portion of the LGE. We propose that the
DLX+;ISL1+
domain gives rise to striatal projection neurons, whereas the DLX+;Er81+
domain contributes interneurons to the olfactory bulb.
Early segregation of striatal projection neuron and olfactory bulb
interneuron precursors
Our results suggest that starting at approximately E12.5 in the
mouse, spatially distinct pools of specified progenitors exist in the
SVZ of the LGE that generate either striatal projection neurons or
olfactory bulb interneurons. A number of facts support the notion that
the
DLX+;ISL1+
domain of the LGE SVZ gives rise to projection neurons of the striatum.
First, many studies have shown that the LGE is the principal source for
striatal projection neurons (Deacon et al., 1994; Olsson et al., 1995,
1997, 1998; Wichterle et al., 2001). Furthermore, the ISL1 expression
in the LGE SVZ is continuous, with differentiating neurons in the
perinatal striatum (Fig. 2D). ISL1 expression in the
striatum is rapidly downregulated postnatally, so that the only
striatal neurons that continue to express detectable levels of ISL1 are
the cholinergic interneurons (Wang and Liu, 2001). This interneuronal
subtype has been shown previously to derive from the adjacent MGE
(Olsson et al., 1998; Marin et al., 2000). The
DLX+;ISL1+
domain is likely to be heterogeneous, because the striatal projection neurons possess at least two distinct subtypes based on neurochemical markers and efferent projections (for review, see Gerfen, 1992).
The present findings support the notion that the
DLX+;Er81+
SVZ domain gives rise to olfactory bulb interneurons, including the
periglomerular cells and at least a portion of the granule cells. Why
do some granule cells display high levels of Er81 and others apparently
none? It may be that all migrating and/or differentiating granule cells
express Er81 and a subpopulation subsequently downregulate it after
differentiation. It is possible, however, that the granule cell
precursors are heterogeneous and a portion of them derive from an area
distinct from the
DLX+;Er81+
domain. Presumably, this would also be in the
DLX+;ISL1
domain, because ISL1-positive cells are not seen in the RMS or olfactory bulb at embryonic or postnatal stages.
Despite their common expression of Er81, periglomerular and granule
cells appear to derive primarily from separate progenitors. Using
retroviral lineage methods, Reid et al. (1999) have shown that
approximately one-half of the clones resulting from infection at early
stages (i.e., E14-E15 in the rat; approximately E12-E13 in the mouse)
contain multiple cell types (e.g., granule and periglomerular cells),
whereas all of those infected at later stages (i.e., E17 in the rat;
E15 in the mouse) contain only one cell type. Interestingly, no clones
were reported to have dispersed between the developing striatum and
olfactory bulb even after infection at early stages. The apparent lack
of dispersion between the olfactory bulb and striatum could be
attributable to a technical problem such as downregulation of the
transgene in one of these regions (Halliday and Cepko, 1992). However,
it could suggest that the separate populations of progenitors in
the LGE SVZ described here arise from differently specified precursor
cells in the VZ.
Although it has been well established that olfactory bulb interneurons
migrate long distances rostrally to take up residence in the olfactory
bulb at postnatal and adult stages (Luskin, 1993; Lois and
Alvarez-Buylla, 1994; Lois et al., 1996; Wichterle et al., 1999), only
recently has it become clear that this strategy is also used at
embryonic stages. Previous studies have shown that significant numbers
of periglomerular and granule cells are generated during the embryonic
period (Hinds, 1968; Bayer, 1983). Using ultrasound-guided
transplantation techniques, Wichterle et al. (2001) have demonstrated
that genetically tagged LGE cells harvested from E13.5 embryos
transplanted to a wild-type LGE of the same developmental stage migrate
rostrally to the olfactory bulb as well as laterally to the adjacent
striatum during embryogenesis. Interestingly, the authors noted that in
embryos in which the donor LGE cells were injected into the anterior
dorsal portion of the LGE, olfactory bulb interneurons in the
glomerular and granule cell layers were consistently found. This
correlates well with the position of the
DLX+;Er81+
domain described here.
Progenitors in the
DLX+;Er81+
domain of the LGE SVZ appear to be heavily dependent on the function of
Pax6 and Gsh2. In the Gsh mutants,
this domain is extinguished, whereas it expands dorsally in the
Pax6 (Sey) mutants. At least in the
Gsh mutants, the altered LGE expression of Er81 correlates
with the loss of Er81-expressing interneurons in the mutant olfactory
bulb. The lack of identifiable olfactory bulbs in Pax6
mutants (Anchan et al., 1997; Jimenez et al., 2000) unfortunately
precludes additional analysis. Progenitors in the
DLX+;ISL1+
domain seem to be differentially affected in Pax6 and
Gsh mutants. Indeed, in Pax6 mutants, the ISL1 expression
domain does not appear to expand dorsally, whereas severe truncations
of this domain are seen in Gsh2 and Gsh1/2 double
mutants (Toresson et al., 2000; Toresson and Campbell, 2001).
The roles of ISL1 and Er81 in generating striatal projection neurons
and olfactory bulb interneurons, respectively, are presently unclear.
Whether they simply mark these populations or actively instruct their
differentiation is an interesting question. Isl1 has been
shown previously to be required for motor neuron development (Pfaff et
al., 1996). Unfortunately, Isl1 homozygous mutants stop developing at approximately E10.5 and die soon after, which is before
striatal neurogenesis is underway (Bayer and Altman, 1995). A targeted
mutation in Er81 has been performed recently (Arber et al.,
2000), and the mutants show defects in wiring between proprioceptive
afferents and motor neurons in the spinal cord; however, no analysis of
the olfactory bulb has yet been reported.
Origins of the postnatal SVZ
The fact that the same neuronal subtypes (i.e., granule and
periglomerular cells) are generated in the olfactory bulb at both embryonic and postnatal time-points would suggest that the progenitors are similar and perhaps share a common origin in the LGE. Indeed cells
of the postnatal and adult SVZ express many molecules typical of LGE
precursors/progenitors, notably, DLX proteins and Er81. It is possible
therefore that the
DLX+;Er81+;ISL1
domain of the LGE SVZ is analogous to, and directly precedes, the
formation of the postnatal/adult SVZ. However, we cannot exclude the
possibility that some of Er81-expressing cells in the adult SVZ may
derive from the
DLX;Er81+
VZ domain of the ventrolateral pallium. Although the most prominent appearance of the postnatal/adult SVZ in coronal sections is in the
dorsal-medial corner of the striatum, recent studies indicate that it
actually exists as an intertwined network, with chains of migrating
neurons covering most of the lateral ventricular wall and ultimately
converging to form the RMS (Doetsch and Alvarez-Buylla, 1996). It is
easy to envision how the
DLX+;Er81+
domain could form the dorsal-medial portion of the SVZ, but the streams of SVZ cells at other positions on the ventricular wall would
have to develop at postnatal stages. In fact, Er81 can be seen in
clusters of SVZ cells at more ventral positions on the adult
ventricular wall in coronal sections (data not shown). Moreover, whole-mount stains of the adult lateral ventricular wall show Er81-positive cells scattered along the dorsoventral extent;
however, obvious chains as demonstrated by TuJ1 (i.e.,
-III-tubulin) staining (Doetsch and Alvarez-Buylla, 1996) are
not evident (our unpublished observations).
Considerable information exists as to the anatomical and
ultrastructural components of the postnatal/adult SVZ. In this respect, the adult SVZ has been shown to be heterogeneous, with chains of
migrating neuroblasts ensheathed by glial cells (Doetsch et al., 1997). The cellular components of the SVZ have been classified into groups based on their molecular and ultrastructural
characteristics (Doetsch et al., 1997). The migrating neuroblasts have
been termed "A" cells, whereas the astroglial cells are called
"B" cells. A third subtype, known as "C" cells, are present in
clusters scattered throughout the SVZ. Only A and B cells are found in
the RMS. Recently, the B cell (i.e., GFAP-positive, putative
astrocyte), or a subpopulation thereof, has been suggested to represent
the stem cell of the postnatal/adult SVZ (Doetsch et al., 1999). C
cells are proposed to represent a transient amplifying population that
gives rise to A cells (for review, see Alvarez-Buylla and
Garcia-Verdugo, 2002). It is currently unclear which subpopulation(s)
of SVZ cells expresses Er81. However, it seems likely that the A cells
(i.e., migrating neuroblasts) would express Er81 given its expression in the RMS and in differentiated neurons.
If the
DLX+;Er81+
domain of the LGE does correspond, at least in part, to the
postnatal/adult SVZ, it provides an exciting possibility to identify
this population of cells already at embryonic stages for more detailed
studies. One important question is why these cells, or their
precursors, continue to undergo neurogenesis throughout the lifetime of
the organism while their striatal counterparts (i.e., the
DLX+;ISL1+
LGE domain) cease to generate neurons around birth.
| |
FOOTNOTES |
Received June 13, 2002; revised Sept. 17, 2002; accepted Sept. 25, 2002.
This work was supported by funds from the Children's Hospital Research
Foundation and the Human Frontiers Science Program (RG160-2000B). We
thank M. Ekker for providing the id6/id5 element, S. Morton and T. Jessell for the Er81 antibody, and G. Panganiban for the
Distalless (DLX) antibody.
Correspondence should be addressed to Kenneth Campbell at the above
address. E-mail: kenneth.campbell{at}chmcc.org.
| |
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TOP
ABSTRACT
Introduction
