1 Developmental Genetics Program and the Department of Cell Biology, The
Skirball Institute of Biomolecular Medicine, New York University Medical
Center, 540 First Avenue, New York, NY 10016, USA
2 Department of Neurology, Institute for Cell Engineering, Johns Hopkins School
of Medicine, Baltimore, MD 21287, USA
* Author for correspondence (e-mail: fishell{at}saturn.med.nyu.edu)
Accepted 3 July 2003
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SUMMARY |
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Key words: Telencephalon, Mouse, Patterning, Pax6, Gsh2, Nkx2.1
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Introduction |
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In the E10.0 mouse telencephalon the expression of Pax6, Gsh2 and Nkx2.1 is
complementary, although, as shown here, this situation exists only
transiently. Nonetheless, this pattern of gene expression provides a reliable
indication of where these genes are required for regional patterning. For
example, Pax6, whose expression at E10.0 is restricted to the dorsal
telencephalon (pallium), regulates many aspects of cortical development,
including specification of progenitor populations
(Stoykova et al., 1996;
Caric et al., 1997
;
Götz et al., 1998
;
Heins et al., 2002
).
Similarly, Nkx2.1 and Gsh2, whose expression at this stage is confined to the
medial and lateral telencephalic domains, respectively, are required for the
proper patterning of each of these regions. In
Nkx2.1/ mutants, the medial ganglionic
eminence (MGE) acquires a lateral ganglionic eminence (LGE) character
(Sussel et al., 1999
).
Moreover, the loss of Gsh2 results in the ectopic expression of
cortical genes throughout much of the LGE
(Corbin et al., 2000
;
Toresson et al., 2000
;
Yun et al., 2001
).
Both the means by which these three genes regulate one another's expression
and their role in establishing regional telencephalic pattern are of
considerable interest. In this regard, it is notable that the
Drosophila gene vnd (an ortholog of Nkx2.1)
functions to repress expansion of lateral fate into the ventral domain of the
Drosophila nerve cord (Chu et
al., 1998; McDonald et al.,
1998
). Furthermore, the Drosophila ind gene (an ortholog
of Gsh2) is essential for repressing dorsal character within the
lateral domain of the fly nerve cord
(Weiss et al., 1998
). Recent
work indicates that similar mechanisms may regulate telencephalic patterning
in mice. For example, the primary function of Pax6 and Gsh2,
with regard to regional patterning of the telencephalon, is to cross-repress
one another. This is evident both from the complementary expansion of
Gsh2 into the normal Pax6 domain in
Pax6/ mutants
(Toresson et al., 2000
;
Yun et al., 2001
), and from
the expansion of Pax6 into the normal territory of Gsh2
expression in Gsh2/ mice
(Corbin et al., 2000
;
Toresson et al., 2000
;
Yun et al., 2001
).
Importantly, telencephalic patterning is largely normal in
Gsh2/;Pax6/
double mutants (Toresson et al.,
2000
).
In this study we have analyzed how the complementary patterns of Pax6, Gsh2
and Nkx2.1 expression observed at E10.0 are generated. Interestingly, we find
that prior to the onset of Gsh2 expression in the telencephalon, Nkx2.1
expression transiently abuts the Pax6 expression domain at E9.5. Prior to the
present study, it was not known whether Nkx2.1 functions to repress either
Pax6 or Gsh2 at the stages of development in which their expression patterns
are complementary, although such interactions might have been predicted based
on the interactions of the orthologs of these genes in the Drosophila
nerve cord (Chu et al., 1998;
McDonald et al., 1998
;
Weiss et al., 1998
).
Surprisingly, we find that these genes do not function cross-repressively to
establish distinct progenitor domains within the telencephalon. Furthermore,
unlike
Gsh2/;Pax6/
double mutants, in which the defects observed in the single mutants are
rescued in the double mutant, regional patterning is further perturbed in
double-mutant mice lacking both Nkx2.1 and Gsh2 gene
function. Indeed, in many aspects, the phenotype observed in
Nkx2.1/;Gsh2/
double mutants resembles that observed in
Shh/ animals. This indicates that these two
genes are primary downstream effectors of the extrinsic signals that act to
establish ventral identity in the telencephalon. Hence, although a small
ventral telencephalic domain persists in
Nkx2.1/;Gsh2/
double mutants, it is clear that patterning in this region is largely
dependent on the combined function of these genes.
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Materials and methods |
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Genotyping
The Nkx2.1 and Gsh2 alleles were genotyped by PCR using
primers previously described (Nery et al.,
2001; Szucsik et al.,
1997
), with the exception that the PCR reaction was enhanced by
the use of GC-rich PCR reagents (Roche). Pax6 (Sey) mice
were identified based on eye morphology
(Hill et al., 1991
) and
confirmed by PCR as previously described
(Grindley et al., 1995
).
Shh mutants were readily identified based on their severe
holoprosencephalic phenotype (Chiang et
al., 1996
). All genomic DNA for PCR was isolated using a QIAamp
Genomic DNA isolation kit (Qiagen).
RNA in situ hybridization
Whole heads (E9.5-E12.5) or isolated brains (E18.5) were fixed at 4°C
in 4% paraformaldehyde for 1-4 hours, rinsed in phosphate-buffered saline
(PBS), cryoprotected overnight in 30% sucrose in PBS and embedded in HistoPrep
(Fisher Scientific). Embedded tissues were sectioned on a cryostat between
12-20 µm. Section RNA in situ hybridization was performed as described
(Schaeren-Wiemers and Gerfin-Moser,
1993; Wilkinson and Nieto,
1993
) using non-radioactive DIG-labelled probes. The following
probes were used in this study: Gad67
(Behar et al., 1994
),
Mash1 (Guillemot and Joyner,
1993
), Ebf1 (Garel et
al., 1997
), Ngn2
(Gradwohl et al., 1996
),
Gsh1 (Valerius et al.,
1995
), Lhx6
(Grigoriou et al., 1998
),
Olig2 (Lu et al.,
2000
), Pdgrfa
(Mercola et al., 1990
) and
Plp/DM20 (Timsit et al.,
1995
). Localization of Dlx2 expression was achieved by
X-gal staining (Corbin et al.,
2000
) of Dlx2-tau-lacZ heterozygous animals
(Corbin et al., 2000
;
Nery et al., 2002
;
Nery et al., 2003
), or by in
situ hybridization using a probe to Dlx2 mRNA
(Porteus et al., 1991
).
Immunohistochemistry
Tissue was processed for immunohistochemistry as described above. The
following antibodies were used for immunofluorescence: mouse anti-Pax6
(1:1000, gift of A. Kawakami), rabbit anti-Pax6 (1:1000, Covance, CA, USA),
mouse anti-Nkx2.1 (1:2000, DAKO, CA, USA), rabbit anti-Nkx2.1 (1:150, Biopat,
Italy), mouse anti-5E1 (anti-Shh, 1:2000, Developmental Studies Hybridoma
Bank, IA, USA), rabbit anti-Crbp1 (1:400, gift of U. Eriksson, Stockholm,
Sweden), rabbit anti-Gsh2 (1:2000, gift of K. Campbell, Cincinnati, OH, USA),
rabbit anti-GABA (1:1000, Sigma, MO, USA), rabbit anti-Calbindin (1:1000,
Calbiochem, CA, USA), rabbit anti-PLAP (1:100, Accurate Chemical, NY, USA).
Secondary antibodies used were: FITC-conjugated donkey anti-rabbit,
Cy3-conjugated donkey anti-rabbit, Cy3-conjugated donkey anti-mouse,
FITC-conjugated donkey anti-mouse (all from Jackson ImmunoResearch, West
Grove, PA, USA). Sections were washed in PBS, blocked for 1 hour with PBS
containing 10% donkey serum and 0.2% Triton X-100. Sections were incubated in
primary antibodies diluted in block (with 10% serum) overnight at 4°C,
then washed three times in PBS and incubated with secondary antibodies diluted
in PBS containing 1% donkey serum and 0.2% Triton X-100 for 1-2 hours at room
temperature in the dark. Fluorescent images were obtained using either a
cooled-CCD camera (Princeton Instruments) and Meta-morph software (Universal
Imaging, West Chester, Pennsylvania) or a confocal microscope (Leica).
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Results |
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At 23 somites (E9.5), before the onset of Gsh2 expression, Nkx2.1 and
Pax6 expression is complementary and forms a clear boundary in the subpallium
(Fig. 1A,C). At this stage, Shh
is expressed in the ventral-most telencephalon nested within the Nkx2.1
positive domain (Fig. 1B,C; see
Fig. S1A at
http://dev.biologists.org/supplemental/).
By 27 somites (
E10.0), a small gap appears between Nkx2.1 and Pax6
expression in the lateral telencephalon
(Fig. 1D). At this stage, Gsh2
expression is first observed in this lateral region in a pattern complementary
to Pax6, and largely complementary to Nkx2.1 expression
(Fig. 1E,F). By E10.5, a larger
gap between Nkx2.1 and Pax6 expression is observed
(Fig. 1G), and Gsh2 expression
expands ventrally into the Nkx2.1 positive domain
(Fig. 1H,I). At E10.5,
expression of Gsh2 and Pax6 partially overlaps
(Fig. 1H)
(Toresson et al., 2000
);
however, by E12.5 this border is more sharply defined
(Rallu et al., 2002a
) (data
not shown).
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At E12.5, the patterning genes Dlx2
(Fig. 5A) and Mash1
(Fig. 5F) are expressed
pan-ventrally. In the absence of Gsh2, expression of both
Dlx2 and Mash1 is lost in the dorsal-most two thirds of the
LGE (Fig. 5B,G)
(Corbin et al., 2000;
Toresson et al., 2000
;
Yun et al., 2001
). In
Nkx2.1/ mutant mice, the domain of
Dlx2 and Mash1 expression is unaffected
(Fig. 5C,H) (Sussel et al., 1999
). In
Nkx2.1/;Gsh2/
double-mutant mice, Dlx2 and Mash1 expression is
significantly reduced (Fig.
5D,I). A similar persistence of Dlx2 and Mash1
expression is observed in the ventral-most region of the mutant telencephalon
of less severely affected Shh mutant mice
(Fig. 5E,J)
(Rallu et al., 2002a
) (K.
Campbell, personal communication).
|
Nkx2.1/;
Gsh2/ double mutant mice display combined
phenotypes of both Nkx2.1/ and
Gsh2/ single mutants
To further compare the phenotype observed in
Nkx2.1/ and
Gsh2/ single versus compound mutants, we
analyzed the expression of LGE (Crbp1, Ebf1) and pallial
(Ngn2, Pax6) specific markers in mice bearing these genotypes.
Expression of the pallial markers Ngn2 and Pax6 normally extends just
across the cortical-striatal sulcus into the dorsolateral LGE
(Fig. 6A,E,M). In
Gsh2/ mutants, expression of both
Ngn2 and Pax6 extends ectopically into all but the ventral third of
the LGE (Fig. 6B,F,N)
(Corbin et al., 2000;
Toresson et al., 2000
;
Yun et al., 2001
). Expression
of Ngn2 and Pax6 in Nkx2.1/ mutants
(Fig. 6C,G,O) resembles that
observed in control embryos. In
Nkx2.1/;Gsh2/
double mutants (Fig. 6D,H,P)
the expansion of Ngn2 and Pax6 into the subpallium is similar to that
observed in Gsh2/ mutants. As in the
Gsh2/ single mutants, this expansion extends
to the level of remnant subpallial gene expression
(Fig. 5D,I,N).
|
Interneuron and oligodendrocyte specification in the absence of
Nkx2.1 and Gsh2
Significant numbers of interneurons and oligodendrocytes arise from the
subpallium, and populate the pallium via tangential migration (reviewed by
Corbin et al., 2001;
Marin and Rubenstein, 2001
).
Furthermore, a number of genes, most prominently Dlx1/2 and
Mash1, have been hypothesized to be involved in the specification of
both cell types (reviewed by Bertrand et
al., 2002
). Reduction in the expression of these genes in mutant
mice lacking both Nkx2.1 and Gsh2 gene function
(Fig. 5) indicates that
specification of oligodendrocytes and interneurons in ventral regions may also
be affected. Gad67, the precursor enzyme for formation of GABA
(Behar et al., 1994
), marks
developing ventral interneuron populations, many of which subsequently undergo
long range tangential migration to the developing cortex. In
Nkx2.1/;Gsh2/
double mutants, Gad67 expression is significantly reduced
(Fig. 7A-D). Interestingly, in
less severely affected Shh/ mutants,
expression of Gad67 persists (Fig.
7E). As Gad67 also marks developing striatal projection
neurons, the status of cortical interneurons in
Nkx2.1/;Gsh2/
double mutant mice was determined by the analysis of calbindin and GABA
expression at E18.5. At a level similar to the cortical interneuron defect in
single Nkx2.1/ mutants
(Sussel et al., 1999
),
generation of cortical interneurons in
Nkx2.1/;Gsh2/
double mutants is markedly reduced (Fig.
8A-D).
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Discussion |
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Interactions between homeodomain genes in establishing the early
telencephalon
In the developing spinal cord, distinct progenitor domains are established
via cross-repressive interactions between Shh-induced class II genes
(Nkx2.2, Nkx2.9, Nkx6.1 and Olig2) and Shh-repressed class I
genes (Dbx1, Dbx2 and Pax6) (reviewed by
Marquardt and Pfaff, 2001;
Kessaris et al., 2001
). To
date, with the exception of the bHLH-containing Olig2 gene, these
genes are members of the homeodomain-containing transcription factor family.
Similarly, in the telencephalon, the homeodomain containing genes
Pax6 and Gsh2 function cross-repressively in the
establishment of the molecular boundary at the cortico-striatal junction
(Toresson et al., 2000
;
Yun et al., 2001
). Despite
this, the present findings demonstrate that, at least in the telencephalon,
the apposing expression patterns of homeodomain proteins are not always
dependent on cross-repression. In the case of Nkx2.1 and Pax6 this is
particularly surprising. In the ventral spinal cord, Nkx (Nkx2.2 and Nkx2.9)
and Pax6 function via a cross-repressive mechanism in establishment of the P3
progenitor domain (Briscoe et al.,
1999
; Briscoe et al.,
2000
). Indeed, previous studies have indicated that these genes
may function cross-repressively in the telencephalon
(Sussel et al., 1999
;
Stoykova et al., 2000
),
implying that the mechanisms involved in patterning of the telencephalon and
spinal cord are analogous (reviewed by
Wilson and Rubenstein, 2000
;
Marin and Rubenstein, 2001
).
However, this proposal was based, in part, on the observations of the effect
of Nkx2.1 and Pax6 loss-of-function mutants at later times
during development (E11-E13). At this stage,
Nkx2.1/ mutants display an expansion of
Pax6 mRNA into the LGE, whereas, in
Pax6/ (Sey/Sey) mutants,
Nkx2.1-positive cells are found ectopically in the LGE in a pattern
resembling an increase in tangential migration. Notably however, by this time
in development, Pax6 and Nkx2.1 expression is separated by the Gsh2 positive
domain and they no longer appose each other. Although these studies reveal
important later functions of Nkx2.1 and Pax6 in the
maintenance of regional pattern and/or cell migration pathways, our results
indicate that at earlier times during development, when their expression is in
apposition, they are not cross-repressive.
The lack of Gsh2 repression by Nkx2.1 is also contrary to predictions based
on the genetic interactions utilized to establish neural progenitor domains in
Drosophila (reviewed by Cornell
and Von Ohlen, 2000). The Drosophila nerve cord is
divided into three distinct neural progenitor domains, dorsal, intermediate
and ventral. The ventral domain expresses the homeodomain transcription factor
vnd (the Nkx ortholog), which functions in a manner analogous to Nkx2.1 by
repressing intermediate character. Despite the similarity in the requirements
for these genes, the failure of Gsh2 expression to expand ventrally in
Nkx2.1/ mutants demonstrates that the
conversion of the MGE to an LGE in Nkx2.1 mutants is not dependent on
Gsh2. Furthermore, if Nkx2.1 acts to suppress LGE character in the
MGE by blocking Gsh2 function by means other than transcriptional repression,
one would predict that the MGE would be rescued in
Nkx2.1/;Gsh2/
double mutants. As shown in Fig.
6K,O, this is not the case, as even in the double mutants the MGE
appears to adopt LGE character.
Convergence of Shh-dependent and Shh-independent signaling at the
level of Nkx2.1 and Gsh2
Although telencephalic patterning is severely affected by the loss of
Shh, recent examination of ventral patterning in
Shh/ mutants has revealed that specific
aspects of ventral patterning can persist in the absence of Shh
(Rallu et al., 2002a) (K.
Campbell, personal communication). Taken as a whole, these data indicate that
the residual ventral patterning in Shh/
mutants is of LGE (i.e. lateral) character. Persistence of panventrally
expressed genes in Shh/ mutants, including
Gsh2, Dlx2, Mash1, and Gad67 and Crbp1, which specifically
marks LGE radial glia, supports this notion. The observation that
Shh-independent processes appear to be required to establish the lateral (LGE)
domain of the telencephalon is reminiscent of the specification of the lateral
VO and V1 interneuron populations in the absence of Shh in the spinal
cord (Pierani et al., 1999
).
Furthermore, although Gsh2 is a downstream target of Shh
signaling, as revealed by gain-of-function studies, in
Shh/ mutant mice expression of this gene
persists, albeit at reduced levels (Rallu
et al., 2002a
). The most compelling evidence for Shh-independent
signaling in the establishment of ventral telencephalic pattern comes from the
rescue of ventral patterning seen in Gli3;Shh or Gli3;Smo
mutants, including complete restoration of the normal Gsh2 and
Nkx2.1 expression domains (Rallu
et al., 2002a
). Although the nature of this signaling at present
remains unclear, Bmp, Fgf, retinoid, Wnt or Nodal signaling all represent
promising candidates for mediating Shh-independent signaling within the
telencephalon (Rallu et al.,
2002b
).
The significant reduction in ventral telencephalic patterning in the
absence of Nkx2.1 and Gsh2 gene function suggests that,
regardless of how Shh-dependent and independent mechanisms cooperate in the
establishment of ventral telencephalic pattern, their actions must converge at
the level of these two homeodomain proteins
(Fig. 9). Despite the
importance of these genes, we observed persistence of some ventral pattern in
the
Nkx2.1/;Gsh2/
compound mutants. This residual pattern may be attributable to the persistence
and expansion of Gsh1 expression in these animals. In single
Gsh2/ mutants, Dlx2 and
Mash1 expression remains in the ventral most aspect of the LGE
(Corbin et al., 2000;
Toresson et al., 2000
;
Yun et al., 2001
). Strikingly,
in compound mutant mice lacking both Gsh1 and Gsh2 gene
function, this domain of Dlx2 and Mash1 expression is
completely lost from the entire LGE at E12.5, indicating that Gsh1 in
combination with Gsh2, regulates patterning in the entire LGE
(Toresson and Campbell, 2001
).
Furthermore, as the MGE is converted to an LGE fate in the absence of
Nkx2.1 gene function (Sussel et
al., 1999
), the remnant Gsh1 expression in
Nkx2.1/;Gsh2/
double mutants is most probably derived not from the MGE, but from the ventral
LGE instead. The observation that the domain of Dlx2 and
Mash1 expression closely matches that of Gsh1 expression
lends further credence to the hypothesis that Gsh1 is responsible for
the residual ventral patterning observed in
Nkx2.1/;Gsh2/
double mutants. Exploration of triple-mutant mice lacking Nkx2.1,
Gsh1 and Gsh2 will be further required to directly address this
hypothesis. Therefore, it may be that the function of Nkx and Gsh genes is all
that is required to pattern the MGE and LGE, and these genes represent the
convergence of Shh-dependent and Shh-independent patterning
(Fig. 9).
|
Our results also give a novel insight into the function of Nkx2.1
and Gsh2 in oligodendrocyte development. Subpallial-derived
oligodendrocytes consist of at least two distinct populations: those that
express Pdgfra and those that express Plp/DM20
(Spassky et al., 1998;
Perez-Villegas et al., 1999
;
Nery et al., 2001
). Our
results reveal that only the PDGFR
-positive population is dependent on
the function of Nkx2.1 and Gsh2; the Plp/DM20
population is unaffected by the loss of these genes. As shown here and
previously (Nery et al.,
2001
), the generation of the PDGFR
-population is positively
regulated by the function of Nkx2.1. Interestingly, this population
also appears to be under negative regulation by Gsh2, as indicated by
the derepression of Pdgfra expression in the MGE and LGE VZ in the
absence of Gsh2. Moreover, ectopic expression of Gsh2 in the medial
domain early in development (E9.5), as revealed by retroviral gain-of-function
experiments, results in the repression of Nkx2.1, an essential regulator of
the generation of PDGFR
-positive oligodendrocytes in the MGE.
Therefore, as Gsh2 may repress the generation of PDGFR
-positive
oligodendrocytes in the developing MGE, specification of these cells may occur
prior to the normal expansion of Gsh2 into the medial domain during
development (<E10.5). In contrast to the generation of
PDGFR
-positive cells, the specification of the Plp/DM20-positive cells
is not dependent on Nkx2.1 or Gsh2. Plp/DM20-positive cells
are generated in the presumptive amygdaloid region of the caudal subpallium.
We have previously revealed that this region is a unique progenitor zone
distinct from the MGE and LGE, and that it is not dependent on the function of
Nkx2.1 and Gsh2 (Nery et
al., 2002
). Therefore, other transcription factor(s) must regulate
the specification of this population. However, these factors are presumably
downstream of Shh, as both PDGFR
- and Plp/DM20-positive oligodendrocyte
populations are absent in Shh/ mutants.
Taken together with previous studies, a hierarchy of gene expression for producing interneurons and oligodendrocytes is becoming apparent. Initiating the generation of these cell types in ventral regions are extrinsic cues, including Shh. These cues result in the expression of homeodomain genes, including Nkx2.1 and Gsh2, that ensure the expression of pan-ventral transcription factors, such as Dlx1/2, Mash1 and Olig2, in the MGE and LGE. These genes, in turn, may act as key effectors in the generation of specific ventral cell types, such as interneurons, and distinct populations of oligodendrocytes.
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ACKNOWLEDGMENTS |
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Footnotes |
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