Department of Neurobiology, Pharmacology and Physiology, Committees on Neurobiology and Developmental Biology, University of Chicago, 947 E 58th Street, MC0926, Chicago, IL 60637, USA
* Author for correspondence (e-mail: egrove{at}drugs.bsd.uchicago.edu)
Accepted 3 September 2004
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SUMMARY |
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Expanding the FGF8 domain suppressed Wnt2b, Wnt3a and Wnt5a expression in the hem. Next to the hem, the hippocampus was shrunken, consistent with its dependence for growth on a hem-derived WNT signal. Maintenance of hem WNT signaling and hippocampal development thus require a constraint on the FGF8 source, which is likely to be supplied by BMP activity. When endogenous BMP signaling is inhibited by noggin, robust Fgf8 expression appears ectopically in the cortical primordium.
Abnormal signaling centers were further investigated in mice lacking the transcription factor EMX2, in which FGF8 activity is increased, WNT expression reduced, and the hippocampus defective. Suggesting that these defects are causally related, sequestering FGF8 in Emx2 homozygous mutants substantially recovered WNT expression in the hem and partially rescued hippocampal development.
Because noggin can induce Fgf8 expression, we examined noggin and BMP signaling in the Emx2 mutant. As the telencephalic vesicle closed, Nog expression was expanded and BMP activity reduced, potentially leading to FGF8 upregulation. Our findings point to a cross-regulation of BMP, FGF, and WNT signaling in the early telencephalon, integrated by EMX2, and required for normal cortical development.
Key words: Cortical area map, In utero electroporation, Emx2 mutant mouse
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Introduction |
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In a classic model of neocortical development
(Rakic, 1988), a `protomap' of
neocortical areas is set up in the cortical neuroepithelium. More recent
findings suggest how such early cortical pattern might be achieved. It has
been proposed that signaling centers in and around the cortical
neuroepithelium secrete members of a select set of powerful embryonic
signaling molecule families. These signaling molecules confer positional
information and regulate regional growth
(Assimacopoulos et al., 2003
;
Garel et al., 2003
;
Grove and Fukuchi-Shimogori,
2003
; O'Leary and Nakagawa,
2002
; Ohkubo et al.,
2002
; Ragsdale and Grove,
2001
; Rubenstein et al.,
1999
; Shimamura and
Rubenstein, 1997
).
Two likely signaling centers for the mouse cortical primordium have been
investigated in some depth. First, an anterior telencephalic source of FGF
proteins, including FGF8 and FGF17 (Bachler
and Neubuser, 2001; Crossley
et al., 2001
; Maruoka et al.,
1998
), imparts position along the anteroposterior (AP) axis of the
developing area map (Fukuchi-Shimogori and
Grove, 2001
; Fukuchi-Shimogori
and Grove, 2003
; Garel et al.,
2003
). If a new FGF8 source is introduced at the posterior pole of
the cortical primordium, posterior cortex is induced to take on a more
anterior fate (Fukuchi-Shimogori and
Grove, 2001
). As might be expected from a classic patterning
theory (Wolpert, 1996
), the
two opposing AP signaling sources induce formation of apparently mirror-image
partial area duplicates (Fukuchi-Shimogori
and Grove, 2001
).
The dorsomedial edge of each cerebral cortical hemisphere, which includes
the `cortical hem', is a source of BMP and WNT proteins
(Furuta et al., 1997;
Grove et al., 1998
;
Lee et al., 2000
). Without a
canonical WNT signal from the hem, the adjacent hippocampus fails to develop
(Galceran et al., 2000
;
Lee et al., 2000
).
Furthermore, when telencephalic BMP activity is partially blocked, few choroid
plexus epithelial cells (CPe) are generated from the medial neuroepithelium
(Hebert et al., 2002
).
Conversely, continuous activation of BMP signaling transforms the entire
cortical primordium into CPe (Panchision
et al., 2001
). These findings indicate a potential for
medial/lateral (M/L) patterning of the cortical neuroepithelium by signals
from the dorsomedial telencephalon.
A devastated cerebral cortex is predicted if cortical signaling centers are
too large, too small, or incorrectly positioned. In the present study, we
therefore searched for mechanisms that could control the size and position of
signaling sources. Classic embryonic signaling centers, studied longer and
more fully, include those in the vertebrate limb bud, which organize the major
axes of the limb and the size of limb components. These classic signaling
centers regulate one another to coordinate limb patterning
(Capdevila and Izpisua Belmonte,
2001; Dahn and Fallon,
2000
; Niswander,
2002
; Riddle et al.,
1993
; Sun et al.,
2002
; Wolpert,
1996
), suggesting that the recently identified cortical patterning
centers may also be controlled by a network of interactions.
More specific guidance comes from studies of dorsal telencephalic signaling
centers in non-mammalian vertebrates
(Crossley et al., 2001;
Ohkubo et al., 2002
;
Shanmugalingam et al., 2000
).
Major dorsal telencephalic circuitry is comparable among mammals, reptiles and
birds (Karten, 1997
;
Medina and Reiner, 2000
),
suggesting homologies at the level of cell type, circuitry and, and in at
least some cases, function. Moreover, telencephalic signaling centers
identified in mouse and chick are strikingly alike, suggesting a further
consistency between the two species in the basic patterning of the
telencephalic AP and ML axes.
The chick telencephalon, like that of the mouse, is exposed to an anterior
source of FGF8 and a dorsomedial source of BMP proteins, both of which
regulate morphological and gene expression patterning
(Crossley et al., 2001;
Golden et al., 1999
;
Ohkubo et al., 2002
). In
addition, Wnt7b and Wnt8b are expressed in the medial
pallium, including a position comparable with that of the mouse cortical hem
(Garda et al., 2002
).
Furthermore, interactions between signaling sources have been analyzed in the
chick: Fgf8 expression is suppressed by BMP signaling, and enhanced
by BMP inhibition (Crossley et al.,
2001
; Ohkubo et al.,
2002
). Thus, chick studies have already provided evidence of
regulation between dorsal telencephalic signaling sources. We sought to extend
this investigation to the mouse cerebral cortex.
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Materials and methods |
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Rescue of the Emx2 mutant cortex
For rescue experiments, the Emx2 mutant mouse line was maintained
on a mixed CD1/C57BL/J6 background. In comparison with mice on a C57BL/J6
background, the addition of the CD1 outbred strain appeared to increase
survival of electroporated embryos. Mice were genotyped as previously
(Pellegrini et al., 1996). The
neocortical and hippocampal phenotype, judged by morphology and gene
expression, did not differ from the Emx2 mutant maintained on a
C57BL/J6 background (Fukuchi-Shimogori and
Grove, 2003
). To test the hypothesis that excess FGF8/17 reduces
WNT expression, leading in turn to hippocampal abnormalities, a construct
encoding a truncated FGF8 receptor (see below) was electroporated into the
anterior cortical primordium of Emx2 mutants at E9.5.
Constructs and histology
Expression plasmids carrying cDNA encoding human placental alkaline
phosphatase (Ap), mouse FGF8 (isoform b) or the soluble, truncated FGFR
receptor 3c (sFGFR3c) were as used previously
(Fukuchi-Shimogori and Grove,
2001; Fukuchi-Shimogori and
Grove, 2003
). EGFP-N1 (Clontech), chick Noggin
and human BMP4 were cloned into the expression vector pEFX
(Agarwala et al., 2001
). Brains
or whole embryos were fixed in 4% paraformaldehyde, and, where needed,
sectioned in the coronal plane with a Leica sliding microtome. Section and
whole-mount in situ hybridization followed described procedures
(Agarwala et al., 2001
;
Grove et al., 1998
).
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Results |
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Electroporated Fgf8 had no observable effect on expression of
Bmp4 in the hem region (Fig.
1D), on expression of Bmp6 or Bmp7 (data not
shown), or on BMP activity assessed by expression of Msx1, a direct
reporter of BMP2 and BMP4 activity (Fig.
1G,H, n=3/3 for Ap and 5/5 for Fgf8).
Reciprocal effects of WNT3A on Fgf8 expression were also not
detected. However, electroporation of Wnt3a at E10.5 or 11.5 promoted
general growth of the cortical hemisphere
(Fukuchi-Shimogori and Grove,
2001) (data not shown).
Excess FGF8 produces an abnormal hippocampus
Hippocampal development requires a WNT signal from the cortical hem
(Galceran et al., 2000;
Lee et al., 2000
). We
therefore examined the hippocampus at E15.5 in brains electroporated with
Ap or Fgf8. Substantial expression of the Ap
transgene (Fig. 2B,H) did not
affect the expression patterns of Wnt3a, Ka1, an early marker of
hippocampal field CA3 (Grove et al.,
1998
; Tole et al.,
1997
), Prox1, an early marker of the dentate gyrus (DG)
(Pleasure et al., 2000
), or
Wnt5a, which is expressed in the hem and the distal hippocampus
(Grove et al., 1998
)
(Fig. 2A,C,G-I). By contrast,
brains efficiently electroporated with Fgf8 showed little or no
expression of Wnt3a or Wnt5a, or the hippocampal field
markers Ka1 and Prox1
(Fig. 2D-F, n=6/6 for
Wnt3a and Ka1; and Fig.
2J-L, n=5/5 for Wnt5a and Prox1).
Efficiency and site of transfection were checked for all brains by transgene
expression. Hippocampal defects in Fgf8-electroporated mice therefore
correlate with ongoing depletion of WNT signaling at the hem.
|
Electroporation at E11.5 of either Bmp4 or Nog had little
or no effect on Fgf8 expression. However, unlike WNT gene expression
in the hem, which is not fully established until E11.5, an anterior FGF8
source is evident very early in telencephalic development, initially at the
interface between ectoderm and neurectoderm, the ANR
(Shimamura and Rubenstein,
1997). Thus, although we found that WNT expression in the hem is
malleable as late as E11.5, anterior Fgf8 expression may not be.
Consequently, mice were electroporated earlier, at E9.5, with EGFP as
a control, or Nog together with EGFP. Embryos were collected
24 hours later and the site of transgene expression was detected by EGFP
fluorescence in each brain (Fig.
3 insets). As in previous experiments, about half of the brains
showed efficient transfection
(Fukuchi-Shimogori and Grove,
2001
; Fukuchi-Shimogori and
Grove, 2003
), which is evident from dense patches of EGFP
fluorescence. In co-electroporated brains with efficient transfection of
EGFP, and presumably also Nog, Fgf8 expression was robustly
upregulated. In some cases, noggin overexpression induced patches of ectopic
Fgf8 in the cortical primordium lateral to the midline
(Fig. 3B,
Fig. 4A, n=3).
Sections through such a brain showed ectopic Fgf8 expression
extending through the entire thickness of the cortical neuroepithelium
(Fig. 4B,C). Normal midline
expression of Fgf8 was also enhanced or extended posteriorly
(Fig. 3B,
Fig. 4A). Diminished BMP
activity after Nog electroporation was inferred by downregulated
expression of Msx2 (Fig.
3G,H, n=9 for Ap and n=5 for
Fgf8) and Msx1 (data not shown), representing a functional
readout of BMP signaling. Consistent with findings above, increased
Fgf8 expression after Nog electroporation was accompanied by
decreased Wnt3a expression in the cortical hem
(Fig. 3E, n=6).
Notably, the effects described were seen in all brains showing efficient
transfection. No such effects were observed in brains in which EGFP
fluorescence could not be detected, or appeared only in scattered cells; nor
were effects seen in brains electroporated with EGFP alone
(Fig. 3A,D,G).
|
|
At E8.75, in wild-type embryos, Nog was expressed at the anterodorsal telencephalic midline, close to the Fgf8-expressing anterior pole (Fig. 5A,I). In Emx2 homozygote mutants, matched to controls for overall development, we observed consistently increased expression of Nog (Fig. 5B,J,K,M, n=4/4). The anterior to posterior extent of Nog expression was roughly three times greater than in wild-type controls (compare Fig. 5B,J,K with A and I), and expression levels appeared increased (Fig. 5L,M).
|
Sequestering FGF8 in Emx2 mutants partially rescues hem WNT expression and hippocampal development
In addition to the defects noted above, the Emx2 mutant shows
dramatic anterior to posterior shifts in neocortical regional pattern
(Bishop et al., 2000;
Bishop et al., 2002
;
Mallamaci et al., 2000
),
similar to those seen after augmentation of the endogenous FGF8 source in
wild-type mice (Fukuchi-Shimogori and
Grove, 2001
). In a previous study, we tested the effect on
neocortical patterning of reducing excess FGF8 in the Emx2 mutant. We
found that this reduction partially rescued neocortical patterning
(Fukuchi-Shimogori and Grove,
2003
). Based on the previous study, and on findings described
above, we hypothesized that excess FGF8 also causes decreased WNT expression
in the hem of Emx2 mutants and consequent abnormalities of the
hippocampus.
To test this possibility, we reduced FGF8 activity, as before, by
electroporation of a truncated FGF receptor. FGFR3c is a high-affinity
receptor for FGF8 and for closely related FGF family members such as FGF17,
which is also overexpressed in the anterior telencephalon of the Emx2
mutant (Fukuchi-Shimogori and Grove,
2003). A soluble, truncated form of the receptor, sFGFR3c, is
presumed to sequester FGF8 and related FGFs, preventing them from binding to
their endogenous receptors
(Fukuchi-Shimogori and Grove,
2001
; Ye et al.,
1998
).
The soluble receptor construct, sFGFR3c, and EGFP were
co-electroporated into the anterior cortical primordium of Emx2
mutants at E9.5 the age at which Wnt3a expression is
initiated at the hem (Lee et al.,
2000). Supporting the hypothesis, 4 days after electroporation,
Emx2 mutant brains that were efficiently transfected showed increased
expression of Wnt3a and Wnt2b in the cortical hem
(Fig. 6C,F, n=8/8).
Brains with sparse or no EGFP-fluorescence continued to show diminished
expression of both WNT genes (Fig.
6B,E).
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Discussion |
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Specifically, we find an antagonism between the WNT and BMP-rich cortical hem, and the anterior telencephalic source of FGF8. FGF8 suppresses WNT gene expression in the cortical hem, and may therefore normally set the anterior boundary of the WNT-rich hem. In turn, Fgf8 expression is suppressed by BMP signaling, which constrains the boundaries of the anterior telencephalic FGF8 source. A particularly striking finding is that a large part of the cortical primordium is competent to express Fgf8. That is, noggin can induce sites of Fgf8 expression far from the telencephalic midline, where Fgf8 is normally expressed. The implication is that BMP activity in the cortical primordium normally provides an extensive and crucial block of Fgf8 expression. The ability of BMP activity to regulate the FGF8 source appears to be time limited, perhaps because the lateral cortical primordium loses competence to express Fgf8.
Cross species comparisons
Our observations of mouse dorsal telencephalic signaling centers fit well
with previous studies in the chick
(Crossley et al., 2001;
Ohkubo et al., 2002
). As
detailed above, telencephalic sources of FGF, WNT and BMP proteins appear in
comparable positions in both species. We confirm in mouse the negative
regulation of an anterior FGF8 source by BMP activity, as well as the broad
competence of the telencephalic primordium to express Fgf8
(Crossley et al., 2001
;
Ohkubo et al., 2002
). Previous
findings indicate shared AP expression gradients of several genes associated
with cerebral cortical pattern, including Emx2
(Crossley et al., 2001
;
Ohkubo et al., 2002
;
Fukuchi-Shimogori and Grove,
2003
; Garel et al.,
2003
). Fgfr3, and COUP-TFI and
COUP-TFII (Nr2f1 and Nr2f2 Mouse Genome
Informatics) (Tsai and Tsai,
1997
; Fukuchi-Shimogori and
Grove, 2001
; Fukuchi-Shimogori
and Grove, 2003
) (C. W. Ragsdale and E. A. Grove, unpublished
observations). The AP gene expression gradients are regulated by FGF8
(Fukuchi-Shimogori and Grove,
2001
; Fukuchi-Shimogori and
Grove, 2003
; Ohkubo et al.,
2002
). These observations suggest that similar mechanisms confer
initial positional information to the dorsal telencephalon in both species.
Indeed, the anterior telencephalic FGF8 source in zebrafish
(Shanmugalingam et al., 2000
)
suggests conservation of patterning mechanism across an even wider range of
vertebrates. Further investigation of dorsal telencephalic patterning in a
variety of species should continue to provide general insights.
Equally important, however, will be determining when and how patterning strategies diverge, given that the dorsal telencephalon has a profoundly different final organization in chick and mouse. In the cerebral cortex of mice or other mammals, functional specialization is organized by subdivision of the cortical sheet into areas. Basic cortical circuitry is organized by cortical lamination. In general, neurons in layer four receive thalamic input, layers two and three project to other cortical areas, and five and six to subcortical structures.
In the chick, as in other birds, basic pallial circuitry is comparable with
that in mammals but its components are distributed as distinct cell types in
different pallial nuclei (Karten,
1997). A particular functional specialization therefore co-opts
parts or all of several nuclei. The avian Wulst is proposed to be most similar
to neocortex (Medina and Reiner,
2000
), containing somatosensory and visual representations. Its
circuitry is organized in pseudolayers, which give a cortex-like appearance.
However, the pseudolayers are in actuality radially adjacent slab-shaped
nuclei (Medina and Reiner,
2000
), so the Wulst also fits the scheme of connected nuclei, in a
particularly orderly manner. Thus, chick and mouse show homology at the level
of dorsal telencephalic cell types, circuits and sensorimotor representations
(Karten, 1997
;
Medina and Reiner, 2000
;
Reiner et al., 2004
), but not
at the level of anatomical organization of circuitry.
Intense debate continues regarding homologies between specific avian and
mammalian dorsal telencephalic structures
(Reiner et al., 2004). A
clearer comparison requires further connectional and physiological
investigation of the avian brain. Comparative studies of embryonic patterning
should also be helpful, at both early (as in the present study) and later
stages of development, as final morphology and connectivity emerge.
Effects of abnormal signaling sources; the Emx2 mutant mouse
Gene transfer experiments with wild-type mice uncover dramatic cortical
patterning defects that occur when signaling centers are misregulated
(Fukuchi-Shimogori and Grove,
2001; Fukuchi-Shimogori and
Grove, 2003
). Augmenting anterior FGF8 shifts the neocortical area
map, suppresses WNT expression in the cortical hem and compromises hippocampal
development. In humans, hippocampal and other cortical abnormalities accompany
certain forms of thanatophoric dysplasia (TDs), devastating disorders caused
by constitutive activation of FGFR3 (Ho et
al., 1984
; Neilson and
Friesel, 1996
; Wongmongkolrit
et al., 1983
). A human hem has been identified
(Abu-Khalil et al., 2004
);
thus, a prediction to be tested is whether defects in hem WNT signaling appear
in TDs and underlie the hippocampal abnormalities.
The Emx2 mutant mouse line provides an informative illustration of
the consequences of signaling center defects. Homozygous mutants display an
expanded FGF8 domain, and predictably, given the present findings, a partial
loss of WNT gene expression in the hem
(Muzio et al., 2002). A
previous study provided evidence that shifts in region-specific gene
expression in the Emx2 mutant neocortex are in part caused by excess
FGF8 (Fukuchi-Shimogori and Grove,
2003
). Findings from the present study indicate that the expanded
FGF8 source in the mutant reduces WNT signaling from the cortical hem, which
in turn could contribute to defective development of the hippocampus.
Emx2 is expressed broadly in the cortical primordium, but its loss does not lead to a broad expansion of Fgf8 expression. Instead, the normally medial and anterior FGF8 domain is enlarged laterally and posteriorly, but retains clear boundaries. Findings from the present study suggest a partial explanation. A likely cause of the expanded FGF8 domain in the Emx2 mutant is early overexpression of noggin at the telencephalic midline, decreasing local BMP activity. BMP inhibition of Fgf8 expression is thereby relieved close to the midline, but not at a distance. Remaining BMP activity may contain further lateral spread of Fgf8 expression.
We suggest that cortically expressed EMX2 influences signaling centers by
direct gene regulation in the cortical primordium. However, an indirect
influence by EMX2 function outside the cortical primordium remains a formal
possibility. Emx2 expression appears at E8-8.5 in rostral brain, and
continues in both the cortical and subcortical forebrain
(Boncinelli et al., 1993),
where EMX2 has diverse roles in development
(Cecchi and Boncinelli, 2000
).
These complexities challenge easy interpretation of specific defects in the
Emx2 mutant. For example, a misrouting of thalamocortical axons,
first ascribed to the absence of EMX2 in the neocortex, may be partially due
to loss of gene function in the ventral telencephalon where the
thalamocortical pathway begins (Bishop et
al., 2002
; Lopez-Bendito et
al., 2002
).
Ultimately, the timing and sites of Emx2 expression that are
crucial to particular aspects of development will be resolved by appropriate
conditional deletions, or regional misexpression, of the gene. A recent
advance has been the generation of a mouse that overexpresses Emx2
under the control of the nestin promotor
(Hamasaki et al., 2004). FGF8
levels appear unaffected, perhaps because Emx2 is overexpressed too
late, yet area boundaries are shifted. These findings, together with our own,
indicate a primary effect of EMX2 on cortical patterning, and a secondary
effect via two signaling sources.
Model of signaling interactions
We propose (Fig. 8) that
early in telencephalic development, EMX2 acts directly or indirectly on noggin
to derepress BMP activity. BMP activity constrains expansion of the anterior
FGF8 source, and keeps the cortical hem clear of FGF8, protecting local WNT
gene expression. Meanwhile, normal levels of midline noggin allow the FGF8
source to be established and maintained. Effectively completing a negative
feedback loop, FGF8 downregulates Emx2 expression. These interactions
help to ensure FGF and WNT/BMP sources of appropriate size, position and
duration to regulate cortical patterning and growth.
|
In conclusion, embryonic signaling centers and their interactions appear crucial for normal cerebral cortical patterning. Experiments using in utero electroporation and analysis of the Emx2 mutant mouse prompt a model in which two signaling centers, the anterior FGF source, and the WNT- and BMP-rich cortical hem interact antagonistically. Both the time dependency of gene misexpression effects and transient gene expression changes in the Emx2 mutant suggest there is a crucial period in early telencephalic development. During this period, the balance of signaling molecules governs the future functional organization of the cerebral cortex.
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ACKNOWLEDGMENTS |
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