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The Journal of Neuroscience, November 1, 2000, 20(21):8042-8050
Pax6 Modulates the Dorsoventral Patterning of
the Mammalian Telencephalon
Anastassia
Stoykova,
Dieter
Treichel,
Marc
Hallonet, and
Peter
Gruss
Max-Planck Institute of Biophysical Chemistry, Department of
Molecular Cell Biology, 37077 Göttingen, Germany
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ABSTRACT |
The Pax6 gene encodes a transcription factor with a
restricted expression in the ventricular zone of the pallium and
subpallium. We tested whether the function of Pax6 is
necessary for the correct patterning and morphogenesis of the
vertebrate telencephalon. Homozygous embryos of the Pax6/Small
eye mutant lack functional PAX6 protein because of a
point mutation of the gene. In the mutant Small eye
embryos we detected a ventralization of the molecular patterning of the
telencephalon at two borders, the pallium/subpallium and the
lateral/medial ganglionic eminence. The results indicate that
Pax6 controls the lateral limit of the expression of
Nkx2.1, Shh, and Lhx6 in
the prechordal neural tube, the telencephalon. This finding is in
agreement with previous studies and supports a model for a common
genetic mechanism for modulation of the dorsoventral patterning of the
prechordal and epichordal CNS. The pattern defects caused by the loss
of Pax6 function result in multiple morphological abnormalities in the
Small eye brain: dysgenesis of the piriform, insular,
and lateral cortices, the claustrum-endopiriform nucleus, and a
failure in the differentiation of a subpopulation of the cortical
precursors. Together the results demonstrate that Pax6 has an essential
role for the modulation of the dorsoventral patterning of the embryonic
telencephalon, influencing thereby the forebrain morphogenesis.
Key words:
Pax6; Small eye; dorsoventral patterning; telencephalon; borders; pallium/subpallium; MGE/LGE
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INTRODUCTION |
The two main subdivisions of the
embryonic telencephalon, pallium (cortex) and subpallium (basal
ganglia), have a distinct molecular patterning and strikingly different
developmental potentials. During development, the initial sheet of
uniform pseudostratified neuroepithelium generates dorsally the
six-layered cortex and ventrally the three eminences, the medial
ganglionic eminence (MGE), lateral ganglionic eminence (LGE), and
caudal ganglionic eminence (CGE), which later differentiate into the
nuclei of the basal ganglia.
The Pax6 gene plays a crucial role in the development of the
vertebrate CNS. The mouse Small eye (allele Sey)
mutation is caused by a point mutation in the Pax6 gene,
resulting in the production of a nonfunctional protein (Hill et al.,
1991 ). The homozygous Small eye animals die at birth with
multiple CNS defects in the eye, forebrain, cerebellum, and spinal cord
(Schmahl et al., 1993; Stoykova et al., 1996; Burrill et al.,
1997; Caric et al., 1997; Ericson et al., 1997; Grindley et al.,
1997; Mastick et al., 1997; Osumi et al., 1997; Engelkamp et al., 1999;
Warren et al., 1999). We have previously found that Pax6 mediates the establishment of distinct adhesive properties between the dorsal and
ventral compartments of the embryonic telencephalon (Stoykova et al.,
1997) and that Pax6 controls the differentiation of the cortical radial
glia cells (Götz et al., 1998). Here we explore the role of
Pax6 in the control of the dorsoventral (DV) regionalization of the telencephalon and the consequences for the brain morphogenesis in loss of Pax6 function.
In the embryonic telencephalon, the expression of Pax6 is
confined to the mitotically active ventricular neuroepithelium (Ne) of
the pallium (Walther and Gruss, 1991). The pallium is classically subdivided into the medial pallium (MP), dorsal pallium (DP), and
lateral pallium (LP), giving rise to the archicortex (hippocampus), neocortex, and paleocortex, respectively. In addition, Pax6
exhibits a particularly strong expression in a small lateralmost region of the ventricular zone of the LGE at the level of the
pallial/subpallial border (Stoykova et al., 1996, 1997). This domain is
intercalated between the neuroepithelium of the striatum and the
lateral pallium (Fig.
1A) and was recently
designated as "ventral pallium" (VP) (Puelles et al., 1999, 2000)
or "intermediate zone" (Smith-Fernandez et al., 1998). The
Pax6 mRNA level shows a lateral-to-medial gradient, being
highest in the region of the VP (Walther and Gruss, 1991; Stoykova et
al., 1997; Puelles et al., 1999). Pax6 is also expressed in
the ventricular zone (VZ) of LGE, although at a very low level (Hallonet et al., 1998; Puelles et al., 1999). A number of
transcription factors and regulatory molecules with a restricted
expression in the embryonic telencephalon are respecting the
pallial/subpallial and MGE/LGE border (for review, see Rubenstein and
Shimamura, 1997; Rubenstein et al., 1998). We examined therefore
whether the strikingly different Pax6 expression levels at
these two boundaries might have a biological function for the
regionalization of the telencephalon. We show in this work that a
similar constellation of genes, including Pax6, Nkx2.1/2.2,
and Shh appears to modulate the DV patterning not only in
the epichordal part of the neural tube (Ericson et al., 1997; Briscoe
et al., 1999), but also in the prechordal part of the CNS, the
telencephalon. Furthermore, we found that the disruption of the normal
DV patterning in the Sey/Sey brain leads to a hypoplasia of
the basolateral cortex, affecting the structures that derive from the
region of the ventral pallium. Our results further suggest that
Pax6 possibly controls the activity of the neural
determination gene Ngn2 in a subpopulation of the cortical
precursors.
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Figure 1.
Ventralization of the neuroepithelium at the
pallio/subpallial border at stage E12.5 in the Sey/Sey
telencephalon. Adjacent coronal sections from the brain of wild-type
(WT; A-D; F,
H; E, G) and homozygous
(Sey/Sey; A'-D'; F',
H'; E', G') littermates at
E12.5 were hybridized with RNA probes for region-specific
markers as indicated. The empty arrowhead in
A points to the morphological corticostriatal sulcus,
whereas the arrows in A,
C, D, and E,
H point to the pallial/subpallial border.
A, The region of the ventral pallium is located between
the arrowhead and the arrow (also in
Figs. 5, 7). The thin
arrows in A and A') point to
early-born Pax6+ cells possibly generated from the VP
and migrating toward the presumptive anlage of the piriform cortex and
anterior amygdala. B, B',
Emx1 is dorsally retracted from the LP in the mutant as
compared with the WT brain. The subpallial markers for the VZ-SVZ are
ectopically expressed in the Ne of the VP, LP, and DP of the
Sey/Sey as illustrated for: Dlx1
(C'), Vax1 (D'), and
Mash1 (G'). The arrowheads
in C' and D' point to the extension of
the Dlx1 and Vax1 expression into a more
dorsal domain within the septum in the mutant brain. In
H', note that the normal expression of
Six3 in the striatal mantle extends laterally into the
mantle of the VP. In E and E',
note that Ngn2 expression is abolished in the VZ of the
VP, strongly suppressed in the LP and in a part of the DP, but appeared
unaffected in the MP (designated by the asterisk below
the MP). The two arrowheads in F point to
the medial limit of Tbr1 expression along the
pallial/subpallial border, thus including in its expression domain the
mantle zone of the VP (the anlage of the ventromedial claustrum;
Puelles et al., 1999). The expression of Tbr1 in this
domain is abolished in the Sey/Sey brain
(F').
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MATERIALS AND METHODS |
Animals. Embryos were derived from crosses of
heterozygous Small eye mice, Sey allele (Roberts,
1967; Hogan et al., 1986) on a C57BL/6JxDBA/2J background. The
point mutation in the Pax6 gene results in the
generation of truncated nonfunctional protein (Hill et al., 1991),
whereas the transcription is not affected, thus allowing us to study
the activity of the gene in the affected brain regions. The day of the
vaginal plug was considered as embryonic day 0.5 (E0.5). The brains of
matched homozygous and wild-type littermates were used for the
expression analysis.
In situ hybridization and immunohistochemistry.
Sectioning, in situ hybridization, and emulsion
autoradiography were performed as previously described (Stoykova and
Gruss, 1994). 35S-labeled sense and
antisense RNA probes were synthesized in the presence of two
radioactive nucleotides from linearized plasmid templates according to
the supplier's instructions (Promega, Madison, WI). Two independent
in situ analyses for each stage were performed. For the
colocalization of the Ngn2 mRNA and the Pax6 antigen first a
nonradioactive in situ hybridization with the
Ngn2 in situ probe was performed on 12 µm
cryostat sections from E13.5 wild-type brain as described by Gradwohl
et al. (1996). For the antibody staining the sections were further
proceeded for immunohistochemistry according to Götz et al.
(1998) using the anti-mouse Pax6 antibody (Development Studies
Hybridoma Bank, Iowa City, IA), 1:200 and "Alexa" 568 goat
anti-mouse conjugate (MoBiTec), 1:500. The terminology is in accordance
with the rat brain atlases of Paxinos et al. (1994), Altman and
Bayer (1995) and Foster (1998).
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RESULTS |
Ventralization of the molecular patterning of the pallial
neuroepithelium in the Pax6/Small eye mutant
telencephalon
To examine whether Pax6 plays a role in the
dorsoventral regionalization at the pallial/subpallial border, we
studied the molecular patterning by in situ hybridization in
sections of E12.5 wild-type (WT) and homozygous Small eye
(Sey/Sey) brains using the following markers:
Emx1 (Simeone et al., 1992) as a dorsal telencephalic
marker, which is expressed in the whole pallium except for the VP
(Puelles et al., 1999, 2000); Pax6 (Walther and Gruss,
1991), Ngn2 (Gradwohl et al., 1996), and Tbr1
(Bulfone et al., 1995; Puelles et al., 1999, 2000) as pallial markers
that include the VP in their expression domains and Dlx1
(Bulfone et al., 1993), Vax1 (Hallonet et al., 1998),
Mash 1 (Guillemot and Joyner, 1993), and Six3 (Oliver
et al., 1995) as ventral telencephalic markers. The comparative
analysis was performed at three rostrocaudal levels of sectioning, and
the detected patterns are illustrated in Figure 1.
At E12.5, Emx1 is expressed in mitotic and postmitotic cells
in the anlage of the medial, dorsal, and lateral pallium (Fig. 1B). In the mutant brain, Emx1
expression was retracted from the depth of the basolateral wall, except
for some Emx1+ cells, located very superficially (Fig.
1B'). The expression of Tbr1 is restricted to early postmitotic cells in the pallium (Bulfone et al., 1995). In
the basolateral telencephalon, the Tbr1 expression extends more medially than Emx1 so that the subventricular zone
(SVZ), submantle, and mantle zone of the VP expresses the
Tbr1, but not the Emx1 gene (Fig.
1F, arrowheads). Thus, the medialmost expression domain of Tbr1 in the basolateral telencephalic wall seems
to consist of postmitotic cells that are generated predominantly from
the neuroepithelium of the VP (Puelles et al., 2000). In Sey/Sey, the expression of Tbr1 was abolished in
the SVZ, submantle, and mantle zone of the VP and appeared less
affected in the postmitotic neurons of the preplate in the DP and LP
(Fig. 1F').
Pax6 is expressed in the VZ of the entire pallium, showing a
particularly strong signal within the region of the VP (Figs. 1A,
2A). In
Sey/Sey the mutant transcripts were much less abundant in
the VP, and the pallial/subpallial border was not well delineated (Figs. 1A', 2A'). The
Pax6 and Ngn2 expression domains overlap in the
pallial VZ (Fig. 1E; see Fig.
5A,B). Interestingly, the expression of
Ngn2 in Sey/Sey was completely abolished in the region of the VP, substantially reduced in the LP and DP, but appeared
at a normal level in the MP (Fig. 1E').
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Figure 2.
Ventralization of the neuroepithelium of the LGE
in Sey/Sey. In situ hybridization on coronal
(A-D') and cross (E, E')
sections from the WT and Sey/Sey brains. Different
markers for the MGE were tested at stages: E13.5
(A-C'), E12.0 (D,D'), and E14.5
(E,E'). In A, note the strikingly
different level of Pax6 expression in the VZ of the VP
and LGE. The arrowheads in A and
A' point to Pax6+ cells that appear to
stream out from the Ne of the VP toward the basolateral telencephalon.
B-C', In the mutant telencephalon, the
lateral limit of the expression of Shh
(B,B') and
Nkx2.1 (C,C') extends from the MGE into
the adjacent territory of the LGE. In D', the
large and small arrows
point to the lateral limit of the strong and the faint ectopic
expression of Nkx2.1 within the VZ of the mutant LGE,
respectively. In E and E', note
the enlarged MGE (which includes at this late stage the adjacent LGE
domain with a ventralized identity) and the differentiating globus
pallidus, labeled by the Nkx2.1 probe (open
arrowhead). F, F', Coronal
sections from E15.5 WT (F) and
Sey/Sey (F') brain at the level of the
preoptic area stained with neutral red, illustrating the
enlarged MGE in the Sey/Sey telencephalon.
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In the WT brain, the transcripts of the subpallial markers Dlx1,
Vax1, and Mash1 in the VZ-SVZ and Six3 in
the mantle zone were clearly not detectable in the VP (Fig.
1C,D,G,H). In the Pax6-deficient brain,
the markers for the ventral telencephalic VZ-SVZ were ectopically
expressed within the Ne of the VP and LP (Fig.
1C',D',G'). Similarly, the expression
of Six3 expanded into the mantle zone of the VP (Fig.
1H'). In addition, the limit of the Dlx1
and Vax1 expression extended more dorsally in the mutant
septum (Fig.
1C,C',D,D',
arrowheads), which appeared enlarged as compared with the
septum of the wild-type brain.
Together these data indicate that in the Sey/Sey
telencephalon, the domain of the VP and LP is ventralized so that the
limit of the Emx1 expression is retracted to a more dorsal
position within the pallium, the expression of Ngn2 and
Tbr1 is abolished in the VZ and SVZ-mantle of the VP,
respectively, and the subpallial markers Dlx1, Vax1, Mash,
and Six3 are ectopically expressed into more dorsal pallial domains.
Ventralization of the subpallial patterning
in Sey/Sey
To test whether the extremely low level of the expression of
Pax6 in the VZ of the entire LGE may have a biological
significance for the patterning of the basal telencephalon, we studied
the expression of several markers for the MGE in sections of WT and Sey/Sey brains at stages E11.5-E14.5. From E10.5 onward,
the proliferative and later on the postmitotic Ne of the MGE begins to
express Shh (Sussel et al., 1999) and Nkx2.1
(Shimamura et al., 1997). The gene Shh encodes a powerful
morphogen with ventralizing activity that can induce the expression of
Nkx2.1 (Ericson et al., 1995; Shimamura et al., 1997) and
Dlx (Kohtz et al., 1998). Furthermore, Shh
can inhibit the activity of the dorsal pattern genes such as
Pax6 (Ericson et al., 1997), Emx1, and
Tbr1 (Kohtz et al., 1998).
As illustrated in Figure 2, B, B', the expression
of Shh at E13.5, whereas normally confined to the submantle
and mantle of the MGE, was expanded into the adjacent territory of the
LGE in Sey/Sey. A similar pattern was seen at stage E12.0 as
well (data not shown). Likewise, the Nkx2.1 expression,
while normally restricted to the germinative Ne and mantle of MGE,
expanded beyond the MGE/LGE border in the mutant brain (Fig.
2C', arrow). At stage E12.0 the ectopic
expression of Nkx2.1 was spread over the VZ of the adjacent LGE domain (Fig. 2D', arrows), which
normally expresses Pax6 at a very low level. Thus, it is
likely that an interaction between Pax6 and
Nkx2.1 genes might contribute for the maintenance of the
MGE/LGE border. At stage E14.5, the Nkx2.1 expression
outlined an enlarged MGE in the mutant brain (Fig.
2E,E'; also F,F').
Next we examined the expression of the LIM-homeobox containing
gene Lhx6, which is assumed to play a specific role in
defining the MGE territory (Grigoriou et al., 1998). The expression of Lhx6 at E12.5 was restricted to a subpopulation of cells in
the SVZ and submantle of the MGE with only a few Lhx6+ cells
in the LGE in a proximal vicinity to the sulcus between MGE and LGE
(Fig. 3A; Wanaka et al., 1997;
Grigoriou et al., 1998). After E13.0, an increasing number of
Lhx6+ cells were observed in the mantle of the wild-type
LGE, accompanied by the appearance of a Lhx6+ layer of cells
in the intermediate zone (IZ) and marginal zone (MZ) of the cortex
(Fig. 3B-D; see also Lavdas et al., 1999; Parnavelas, 2000). In Sey/Sey, already at E12.5 the expression of
Lhx6 in the LGE was much more widespread, strongly
suggesting that the mutant LGE contains a higher number of
Lhx6+ cells (Fig. 3A'). To further characterize
this pattern defect, in situ hybridization analysis was
performed on sections from E14.0 wild-type and Sey/Sey brains at different rostrocaudal levels. The expression of
Lhx6 along the entire rostrocaudal axis was much more
abundant in the mutant as compared with the wild-type LGE (Fig.
3B-D'). Furthermore, while present in the MZ of the
Sey/Sey cortex, Lhx6+ cells were not detectable
in the lower part of the mutant cortical plate (Fig.
3B'-D'). In accordance with previous data
showing that the Lhx6+ cells originate mainly from the Ne of
the MGE (Grigoriou et al., 1998) at a very rostral level the WT septum
contained only a few Lhx6+ cells (Fig. 3B). In
contrast, the SVZ-submantle of the septum in Sey/Sey was
abundantly populated with Lhx6+cells that seem to migrate
directly into the mutant LGE (Fig. 3B'). Thus, in Pax6 loss
of function the Ne of the rostral septum and MGE appears to produce a
higher number of Lhx6+ cells that migrate into the territory
LGE, but these cells fail to populate the lower part of the mutant
cortical plate. Different possibilities may account for the observed
wider expression of Lhx6 in the basolateral telencephalon in
Sey/Sey: (1) enhancement of the rate of the Lhx6 mRNA synthesis implicating a transcriptional regulation between Pax6 and Lhx6; (2) increase of the number of the
generated Lhx6+ cells and/or enhanced ventrodorsal cell
migration between the MGE and LGE as a result of the ventralization of
a part of the Ne of LGE, as noticed above; and (3) accumulation
of Lhx6+ cells within the mutant LGE because of a
malformation of the corticopetal axons (Kawano et al., 1999) that
normally help the subpallial cells in their tangential migration toward
the cortex. Further experimentation will be required to definitively
distinguish between these possibilities.
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Figure 3.
Expression of Lhx6 in the
basolateral telencephalon in wild-type and Sey/Sey
brain. A, A', Coronal sections from E12.5
wild-type (A) and mutant (A')
brain. Note the enhanced number of Lhx6+ cells in the
mutant LGE. B-D', Coronal sections from E14.0 wild-type
(B-D) and mutant
(B'-D') brain at different rostrocaudal
levels. The open and the thin
arrows in B point to a Lhx6+
layer of cells in the intermediate and marginal zones of the CP,
respectively. In all levels note the enhanced expression of
Lhx6 in the LGE in the mutant as compared with the WT
brain and the lack of Lhx6+ cells in the lower part of
the Sey/Sey CP. B, B', Note the increased
expression of Lhx6 in the rostral septum in
Sey/Sey (open arrowhead) from where more
Lhx6+ cells seem to populate directly the LGE.
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Taken together, the results from the performed analysis of the
patterning of the basal telencephalon indicate that in the lack of a
functional Pax6 protein a more dorsal domain (LGE) of the basal
telencephalon achieves characteristics of a more ventral domain (MGE).
Defects in the rostral basolateral telencephalon of the
Sey/Sey brain
The origin of the telencephalic basolateral structures is still
under debate. Morphological studies suggested that whereas the
claustrum has a neocortical origin, the endopiriform nucleus and
piriform cortex originate from the Ne of the corticostriatal wedge
(Bayer and Altman, 1991a) and/or from the Ne of the LGE (Valverde and
Santacana, 1994; De Carlos et al., 1996).
At stage E12.5, cells expressing Pax6 or Tbr1
appear to extend out from the Ne of the VP toward the basolateral
telencephalon (Fig. 1A,F; see Fig. 7). To study which
basolateral structures were specifically patterned by either of the two
pallial markers, we examined the patterning at stage E18.5. In
agreement with Bulfone et al. (1995), Tbr1 transcripts were
detected in postmitotic cells of the neocortex and paleocortex,
classical claustrum (Cl) (Fig. 4A,C,F), and the
dense layer II of the piriform cortex (Fig. 4B, open
arrowhead). Recent results indicate that the classical claustrum is a derivative of the "dorsolateral claustrum" whose precursors are possibly generated from the Ne of the
Tbr1+/Emx1+ lateral pallium (Puelles et al.,
1999, 2000). Rostrally, Pax6 was not expressed in the
differentiating classical claustrum (Fig. 4D). However, Pax6 transcripts were detected in the presumptive
domain of the olfactory tubercle (Tu) and in the ventral part
(presumptive layer I) of the piriform cortex (Fig. 4E,
filled arrowhead). In addition, Pax6 was expressed in a
region, which has been designated by different authors as the
endopiriform nucleus, anterior amygdalar area, ventral pallidum, and/or
lateral striatal area (Fig. 4E,F, arrow). At early
developmental stages this domain was referred to as the "ventromedial
claustrum", a derivative of the VP (Fig. 1F,
arrowheads) (for discussion, see Puelles et al., 1999, 2000). Results from autoradiographic studies indicated that early-born cells
from the Ne of the corticostriatal wedge (included in the territory of
VP) are divided by the growing tip of the cortical plate at late
developmental stages into a superficial part corresponding to layer I
and a deep part, corresponding to cells located in the adult layer III
of the piriform cortex (Valverde and Santacana, 1994). Thus, our
results suggest that the early- and the late-born constituents of the
piriform cortex (the primary olfactory cortex) are differentially
patterned by Pax6 and Tbr1.
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Figure 4.
Differently patterned structures by
Pax6 and Tbr1 are distorted in the
Sey/Sey basolateral telencephalon. A, B, D,
E, Adjacent coronal sections from the E18.5 WT brain were
hybridized with probes for Tbr1 (A, B)
and Pax6 (D, E). C is a
bright-field picture of an adjacent section to the section
(B) after hematoxylin-eosin (HE)
staining. F is a close-up of C for the
indicated field. A, B, Tbr1 expression is
detected in the differentiating claustrum proper
(Cl) and in the dense layer II (B, open
arrowhead) of the piriform cortex. D, E,
Pax6 is expressed in the olfactory tuberculum
(Tu), in the ventral part (presumptive layer I) of the
piriform cortex (E, arrowhead), and in the presumptive
anlage of the anterior amygdala-endopiriform nucleus, a thin
arrow in E and F. In
E, note that the dense layer of the piriform cortex is
Pax6-negative (open arrowhead).
G-J are adjacent coronal sections from the E18.5
Sey/Sey brain, hybridized with Tbr1
(G) and Pax6 (I) probes or stained
with HE (H, J). In C,
F, H, and J
note that in the mutant brain, the piriform cortex, the claustrum
proper, the endopiriform nucleus-anterior amygdala and the reservoir
(r) are not distinguishable. The dark-stained
structures in H and J are cells from the
pallial germinative neuroepithelium that form clumps (or a thick band
at other levels) located all along the pathway of the lateral migratory
stream (Fig. 5) in the Sey/Sey pallium.
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As illustrated in Figure 4, the piriform cortex, the claustrum (assumed
to represent the deep layers of the insular cortex), the endopiriform
nucleus, and the reservoirs cells (r) (Bayer and Altman 1991a,b) were
not detectable in the rostral Sey/Sey telencephalon.
Likewise, the lateral cortex including the prospective insular cortex
was severely disorganized without a recognizable cortical plate at a
very rostral level (Fig. 4C,H). Cells expressing defective Pax6 transcripts were detectable in the stream
that extends from the Ne of the VP along the pallial/subpallial border (Fig. 1A'), implicating that Pax6 would
not have a cell autonomous function for the generation of the
early-born cells of the piriform cortex. We assume rather that the
dysgenesis of the piriform, lateral cortex and claustrum in the
Sey/Sey telencephalon is a consequence of the prominent
ventralization of the molecular patterning of the VP in
Sey/Sey as demonstrated in this work.
Defects in the differentiation of the cortical plate
in Sey/Sey
The intriguing finding that at E12.5 Pax6 and
Ngn2 have overlapping expression domains and that the
activity of Ngn2 was downregulated within the
Sey/Sey pallium was confirmed also later in development (Fig. 5). Recent data (Hartfuss et al.,
2000) indicated that a subpopulation of acutely dissociated cortical
progenitors colocalize Ngn2 and Pax6, implicating that a direct
regulation between the two genes might cause the lack of the Ngn2
expression in the VP-LP. The performed double in situ and
immunolabeling for Ngn2 and Pax6 revealed at E13.5 a nuclear
signal for Pax6 only in a limited number of the Ngn2+
pallial cells, including the region of VP and LP (Fig. 5D).
These data suggest that the observed lack of Ngn2 expression
might be a consequence of both, the ventralization of the
neuroepithelium as described above and possibly involving also a direct
gene regulation in a subset of the cortical progenitors. We assume
therefore that a region-specific downregulation of the activity of the
proneural gene Ngn2 in the ventrolateral pallium might
contribute to the complex cortical phenotype in Sey/Sey.
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Figure 5.
Inhibition of Ngn2 activity in a
subpopulation of the cortical progenitors in Sey/Sey.
Coronal sections from E16.5 wild-type (A, B) and
Sey/Sey (A', B') brain
hybridized with Ngn2 (A,
A') and Pax6 (B,
B') probes. In A note that the region of
the VP in the VZ of the LGE is still distinguishable at this late
developmental stage. In the mutant, the expression of
Ngn2 is completely abolished from the region of the VP
and LP, severely repressed in the DP, but appears unaffected in the MP.
In B' note that the enlarged VZ-SVZ in the
Sey/Sey pallium is expressing abundantly the mutant
Pax6 mRNA (B'). C, D,
Coronal sections from E13.5 WT brain were double-labeled by in
situ histochemistry with the Ngn2 antisense RNA
probe (blue cytoplasmic staining) and by
immunohistochemistry with the Pax6 antibody (red nuclear
stain). The enlarged inserts are higher magnifications
showing that some Pax6-immunoreactive cortical progenitors express
Ngn2 mRNA (open arrowheads). The
filled arrowheads point to progenitors that are only
Ngn2+. D is a composite picture of
C and the Pax6 immunostaining; the overlay has been done
in Adobe Photoshop.
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A prominent feature of the Sey/Sey pallium is the thin
cortical plate (CP) and the enlarged germinative neuroepithelium
(VZ-SVZ) that occupies the IZ domain (Fig.
6A,A'; for discussion,
see also Warren et al., 1999). Highly accumulated cells appear adherent to each other all along the lateral migratory stream (Fig.
6B'), a pathway that normally carries postmitotic
cells populating the basolateral cortex. At stage E14.5, the early
differentiation markers Tbr1 and SorLA showed
only a faint expression in the superficial zone of the forming CP, but
were not detected in the mutant VZ-SVZ (data not shown). We tested the
differentiation of the mutant cortex further at stage E18.5 using the
available layer-specific markers: Emx1 and Tbr1
for all layers of the cortex (Bulfone et al., 1995), Otx1
for layer V-VI (Frantz et al., 1994), mSorLA for layers
V-II (Hermans-BorgMeyer et al., 1998; our unpublished observations) and reelin for the MZ (D'Arcangelo et
al., 1995; Ogawa et al., 1995). In the abortive CP, the Emx1,
mSorLa, and Otx1 showed a diffuse expression at a
similar strength (Fig. 6C',F',G'), and
the Tbr1 transcripts accumulated in the lower part of the CP
(Fig. 6E'; Warren et al., 1999). The VZ and SVZ of
the mutant pallium was labeled by the Emx1 and
Otx1 probes (Fig. 6C',G', arrowheads). In contrast, the expression of Tbr1
(Fig. 6E') and SorLA (Fig.
6F') within the enlarged VZ-SVZ was abolished,
most strongly within the region of VP and LP (Fig.
6E',F', asterisks) as compared
with the dorsomedial SVZ. This finding is consistent with the noticed
above region specific inhibition of the Ngn2 activity in
Sey/Sey. Together, these data suggest that the inhibition of
the Ngn2 activity in the Sey/Sey pallium might
prevent/or causes a delay in the differentiation of a subpopulation of
the cortical progenitors (mostly within the ventrolateral pallial
domain) that fail to migrate and accumulate within the pathological
germinative Ne.
View larger version (107K):
[in this window]
[in a new window]
|
Figure 6.
Failure in the differentiation of the cortical
plate in Sey/Sey. Coronal sections at a rostral level
from E18.5 WT (B-D) and Sey/Sey
(B'-D') brain were hybridized with
different cortical markers, as indicated. A and
A' are Nissl-stained sections from a WT and a mutant
brain illustrating the severe abnormalities of the pallium in the
mutant: an enlarged germinative zone (VZ-SVZ), a lack
of a delineated intermediate zone (IZ) and subplate
(SP), a thin cortical plate (CP) without
radial alignment of the cells, and a wide and hypercellular marginal
zone (MZ). The asterisks in
E' and F' point to the germinative Ne of
the VP + LP that are compressed by the growing striatum and therefore
not easily distinguishable; the thin arrow in
B points to the lateral migratory stream (LMS). In
B' note the Pax6-positive VZ-SVZ in the
mutant pallium, which expands within the domain of the VP, LP, DP, in
the hilus (h) of the LMS, but not in the MP. In
C' and G' note that the expression of
Emx1 and Otx1 in the pallial VZ-SVZ
(arrowheads) of Sey/Sey is detectable.
E, F, In the WT brain, Tbr1 and
mSorLa are expressed in the SVZ (empty
arrowhead) of the entire pallium and their expression outline
the piriform cortex as well. E', F', In
Sey/Sey, the expression of Tbr1 and
SorLA is abolished in the enlarged SVZ of the VP-LP
(asterisks), except for the region of the MP. In the
basolateral telencephalon note the disorganization of the lateral
insular and piriform cortex. C',
F', G', Emx1, Otx1, and
mSorLa show diffuse expression in the abortive mutant
CP, whereas the Tbr1 transcripts are accumulated
in the lower part of the CP (E'). In
D' note the stronger expression of reelin
in the mutant MZ. The arrowhead in D
points to a layer of reelin+ cells in the CP that is not
detectable in the Sey/Sey cortex
(D').
|
|
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[in this window]
[in a new window]
|
Figure 7.
Schematic representation of the DV pattern defects
in the telencephalon of the Pax6/Small
eye mutant. The scheme illustrates that in the absence of
functional Pax6 protein, the molecular patterning of the embryonic
telencephalon is ventralized at the level of the pallial/subpallial and
MGE/LGE borders. The drawing is based on the proposed subdivision of
the telencephalic Ne (Puelles et al., 1999, 2000) and the results
obtained from the expression analysis performed on coronal sections at
a rostral level of the E12.5 wild-type (WT) and
homozygous Small eye (Sey/Sey) brain. The
pallial and subpallial markers have been color-coded as indicated. The
arrow points to the morphological corticostriatal
sulcus. The filled arrowhead points to the
pallial/subpallial border, from where a of Pax6+ stream
of cells (red dots) and Tbr1+
(black dots) cells migrate toward the basolateral
telencephalon as discussed in the text. Noteworthy, results from a very
recent homology study in chick and mouse suggest that the
Pax6+ cells migrate within the striatal territory
(Puelles et al., 2000). The open arrowhead points to the
boundary between the MGE (pallidum) and the LGE (striatum).
|
|
Given the key role of reelin in the laminar cortical development
(Lambert de Rouvroit and Goffinet, 1998), it is of special interest to
note that whereas the reelin expression in the
Sey/Sey MZ was at a higher level as compared with the
wild-type brain, the reelin transcripts were lacking from
the IZ of the pallium in the mutant brain (Fig.
6D',D, arrowhead).
| |
DISCUSSION |
Pax6 modulates the DV regionalization of the
neuroepithelium along the entire anteroposterior axis of the
developing CNS
Accumulating evidence indicates that the expression of
Shh in the axial mesendoderm is essential for the ventral
specification of the developing CNS, including the forebrain (Ericson
et al., 1995; Chiang et al., 1996; Rubenstein and Shimamura,
1997). In the ventral neural tube the Shh signal secreted from the
floor plate mediates a long-range repression of the Pax6
level, forming thereby four zones of distinct progenitors, a most
ventral Pax6 /Nkx2.2+ domain and progressively more
dorsally located domains with low, moderate, and high levels of
Pax6 expression (Ericson et al., 1995, 1997). The
progenitors of these domains generate distinct neuronal populations of
the motor neurons and the three columns of interneurons. Our analysis
revealed a similar characteristic in three ventrodorsal domains of the
telencephalic neuroepithelium for the expression of Pax6 and
Nkx2.1 which is another member of the Nkx gene family with a
restricted expression in the anlage of the MGE (Price et al., 1992;
Shimamura et al., 1995; Sussel et al., 1999). It should be noted
however that the "dorsoventral" terminology used to describe our
observations is preliminary because the topological relationship of the
telencephalic subdivisions is still an open question (for discussion,
see Rubenstein et al., 1998).
We found that the most ventrally located domain, the VZ of the MGE,
that generates the cells of the pallidum is a Pax6, but Nkx2.1+/Dlx1,2+/Vax1+/Mash1+
region. In the MGE, Shh is initially expressed in the
VZ (Sussel et al., 1999), and later it is expressed in the SVZ
and mantle zone. The next domain is the VZ of the LGE, which produces
the striatum. It expresses Pax6 at a very low level and is
Nkx2.1/Dlx1,2+/Vax1+/Mash1+. The domain of the
VP is the third zone, located further dorsally. It contributes to the
generation of the claustrum-endopiriform nucleus, the piriform cortex,
and a part of the amygdala (Bayer and Altman, 1991; for further
discussion see Puelles at al., 2000). Here the expression of
Pax6 (and Ngn2 as well) is very high,
whereas the transcripts of Nkx2.1, Dlx1, Vax1, and
Mash1 are absent.
In the caudal neural tube, the loss of Pax6 function leads to a dorsal
expansion of ventral markers and to a change of the cell fate (Ericson
et al., 1997). Likewise we found that the Pax6 mutation leads to an
expansion of the expression of the MGE marker genes Shh,
Nkx2.1, and Lhx6 into the territory of the more
dorsally located LGE. This pattern defect appears to result in the
alteration of the regional identity of the adjacent LGE area reflected
in an enlargement of the MGE territory at midgestation and
underdevelopment of the striatum later on a puzzling morphological
phenotype for the Pax6 mutant brain for a long time (Glaser et al.,
1994). We found further that the ventralization of the Ne of the VP,
where Pax6 is expressed at a very high level, causes defects
in the generation of the piriform, rostral lateral (insular) cortex, and the claustrum-endopiriform nucleus. These defects are reminiscent to observations in the Sey/Sey hindbrain and spinal cord
where the columns of the dorsally and more ventrally located neurons, produced by domains with a very high and low level of Pax6
expression, are either missing or show an altered identity,
respectively (Burrill et al., 1997; Ericson et al., 1997). Thus,
in Pax6 loss of function in appears that domains that normally have a
comparable level of Pax6 expression, show similar
morphological disturbances in the epichordal and prechordal part of the
CNS as a result of the ventralization of the molecular identity of
adjacent regions. These results indicate that the level of Pax6
expression is an essential determinant of the DV regionalization of the
Ne along the entire anteroposterior axis of the developing CNS.
In the spinal cord of Nkx2.2/ mice the fate
of the most ventral column of neurons is dorsalized into the fate of
the somatic motoneurons, but without a change in the Pax6
expressiona fact implicating that Nkx2.2 has a decisive
role for interpreting the ventralizing activity of the Shh protein
produced by the notochord and floor plate (Briscoe et al., 1999).
Although Shh, which is produced by the rostral mesendoderm, is an
essential factor for establishing the ventral identity in the forebrain
(Ericson et al., 1995; Shimamura and Rubenstein, 1997), the final
specification of the DV domains in the telencephalon seems to include
additional mechanisms. The expression of Nkx2.1 and
Shh in the MGE and Pax6 in the pallium appears
almost simultaneously at ~E10.5 (Hentges et al., 1999). In Pax6 loss
of function we observed ectopic expression of both Shh and
Nkx2.1 into more dorsal telencephalic domains. A recent
analysis of Nkx2.1/ mice revealed opposite pattern defects as compared with the Small eye telencephalon (Sussel
et al., 1999). In these mice, the lateral domain of the MGE is
dorsalized showing ectopic expression of Pax6, whereas the
expression of Shh in the MGE is suppressed. The alteration
of the patterning leads to a lack of the globus pallidus and an
enlargement of the striatum. Thus, in the Sey/Sey and
Nkx2.1/ mutants, although the anlage of the MGE and LGE
are specified presumably by the ventralizing activity of the
mesendodermal Shh, these structures show a complementary DV pattern and
morphological defects in the adjacent domains of the MGE or LGE. It is
worthy to note that in the absence of the low level expression of
Pax6 in the VZ of the LGE, the dorsal ectopic expression of
Nkx2.1 includes the VZ of a part of the LGE. Together, these
data suggest that either a direct regulation of the activity of these
genes or protein-protein interactions between their products might
contribute for the maintenance of the MGE/LGE border in the telencephalon.
Pax6 and the patterning of the cortex
The development of the cortex is severely affected in the
Sey/Sey mutant: the CP is hypocellular without radial
alignment of the cells, whereas the germinative neuroepithelium
(VZ-SVZ) is enlarged and consists of accumulated precursors in large
clumps that occupy the area of the IZ (Schmahl et al., 1993; Warren and Price, 1999). These cells show a high level of expression of the mutant
Pax6 message (Stoykova et al., 1997; this study) and active incorporation of BrdU after pulse labeling at early (E10-E12.5) (Warren et al., 1999) and later (E12.5-E18.5) stages (Brunjes et al.,
1998; Götz et al., 1998).
We show in this work a severe defect of the DV patterning in the
Sey/Sey telencephalon. As a result of the early
developmental ventralization of the NE at the pallial/subpallial
border, the morphogenesis of the basolateral cortex appears to be
strongly affected, as shown by the malformation of the claustrum,
endopiriform nucleus, piriform, and lateral cortex.
From E14.5 onward, the pallium of the Sey/Sey mutant fails
to properly differentiate. The accumulated cells in the mutant VZ-SVZ
express the neuron-specific marker TuJ1 (Caric et al., 1997). However,
the expression of the differentiation markers Tbr1,
mSorLa, and Emx1 were not detected in the SVZ of
the ventrolateral and dorsal pallium, but being preserved in the MP and
in the abortive cortical plate. This suggests that only a portion of
the later cortical progenitors are either not generated or they are
unable to properly differentiate in the Sey/Sey cortex. A
similar regional inhibition of the activity of the Ngn2 gene
was detected in the VZ of the mutant pallium. Ngns are
vertebrate neuronal determination genes encoding for basic
helix-loop-helix transcription factors, essential for the neurogenesis,
including the cortex (Ma et al., 1996; 1999; Cai et al., 2000). Our
previous results indicated that the expression of Pax6 is a
characteristic trait of the cortical RC2+ radial glial cells with an
essential role for their differentiation (Götz et al., 1998). The
cortical radial glial cells might have a neurogenic potential
(Alvarez-Buylla et al., 1990; Lendahl et al., 1990; Gray and Sanes,
1992). In accordance with recent results indicating that Ngn2 is
detected only in those Pax6+/RC2+ radial glial cells, that contain
neither the astrocyte-specific glutamate transporter (GLAST) nor the
brain- lipid-binding protein (BLBP) (Götz, 2000; Hartfuss
et al., 2000) we show here that at E13.5 the expression of
Ngn2 and Pax6 normally colocalizes only in some cortical
progenitors. Most intriguingly, the misexpression of Ngn2 in
the cortical progenitor cells results in the production of neurons (Cai
et al., 2000). Furthermore, isolated radial glial cells from
Sey/Sey cortex generated in vitro only 44% of
the neuronal clones produced by the WT radial glial cells (Malatesta
and Götz, 2000). Thus, our results and the literature data
support the possibility that the differentiation of not all cortical
precursors in the Sey/Sey pallium is affected; indeed the
mutant CP shows expression of all tested cortical markers. We favor
rather the idea that only a portion, mainly the Ngn2+/Pax6+ progenitors
of the ventrolateral pallium are hampered to differentiate in Pax6 loss
of function.
Accumulating evidence indicates that some postmitotic cells born in the
subpallium invade the pallium. Thus, a part of the cortical
interneurons are produced in the subpallial Ne and populate through a
tangential migration the CP as postmitotic Dlx-, GABA-, GAD67-, Lhx6-,
calbindin-, calretinin-, or reelin-positive cells (for review, see
Parnavelas, 2000). The absence of Dlx1/2 (Anderson et al.,
1997a,b) and Mash1 (Casarosa et al., 1999) in the MGE/LGE leads to an almost complete loss of the GAD67+ cells in the CP or in
the MZ, respectively, whereas the loss of Nkx2.1 in the MGE
(Sussel et al., 1999) is associated with absence of calbin-din+ cells. We show in this work that early in development the proliferative Ne of the VP and LP in Sey/Sey expresses ectopically
Dlx1, Mash1, Vax1, and Six3, whereas
the restricted expression of Nkx2.1 and Lhx6 to
the MGE expands into the adjacent LGE territory. Therefore it is likely
that the ventralized Ne in the basal telencephalon of
Sey/Sey produces progenitors with altered identity,
increasing thereby the portion of the subpallial cells that migrate
into the cortex. This is in line with data showing that the lateral telencephalon of Sey/Sey contains twice as much postmitotic
GABA+, calbindin+ and calretinin+ cells as compared with the wild-type littermates (Chapouton et al., 1999). Thus, the defects of the dorsoventral patterning of the telencephalic neuroepithelium in Pax6
loss of function are part of the complex cortical phenotype of the
Small eye mutant.
| |
FOOTNOTES |
Received April 6, 2000; revised Aug. 11, 2000; accepted Aug. 14, 2000.
This work was supported by the Max-Planck-Gesellschaft. We thank A. Simeone, M. Price, F. Guillemot, V. Pachnis, A. Bulfone, Chica
Schaller, A. McMahon, and V. Tarabykin for providing us with
Emx1, Emx2, and Otx1,
Dlx1, and Nkx2.1, Mash1,
Ngn1, and Ngn2, Lhx6, Tbr1,
SorLa, Shh, and reelin
probes for the in situ analysis. We thank L. Puelles and
M. Götz for fruitful discussions. The excellent technical
assistance of S. Eckert is highly acknowledged. Thanks are due to S. Heinemann for correcting this manuscript.
Correspondence should be addressed to Anastassia Stoykova, Max-Planck
Institute of Biophysical Chemistry, Department of Molecular Cell
Biology, 37077 Göttingen, Germany. E-mail: astoyko{at}gwdg.de.
Dr. Hallonet's present address: Institut de Génétique et
de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, B.P. 163, 67404 Illkirch Cedex, France.
| |
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T. Theil, S. Aydin, S. Koch, L. Grotewold, and U. Ruther
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[Abstract]
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H. Toresson and K. Campbell
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Molecular Characterization of Pax62Neu Through Pax610Neu: An Extension of the Pax6 Allelic Series and the Identification of Two Possible Hypomorph Alleles in the Mouse Mus musculus
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M. McCarthy, D. H. Turnbull, C. A. Walsh, and G. Fishell
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Pax6 regulates granule cell polarization during parallel fiber formation in the developing cerebellum
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V. Tarabykin, A. Stoykova, N. Usman, and P. Gruss
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Development,
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Y. Shimoda, Y. Tajima, T. Osanai, A. Katsume, M. Kohara, T. Kudo, H. Narimatsu, N. Takashima, Y. Ishii, S. Nakamura, et al.
Pax6 Controls the Expression of Lewis x Epitope in the Embryonic Forebrain by Regulating alpha 1,3-Fucosyltransferase IX Expression
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TOP
ABSTRACT
INTRODUCTION
