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First published online 3 July 2006
doi: 10.1242/dev.02465
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1 Departments of Neuroscience and Molecular Genetics, Albert Einstein College of
Medicine, 1410 Pelham Parkway South, Bronx, NY 10461, USA.
2 Department of Biological Sciences, Stanford University, Stanford, CA 94305,
USA.
3 Department of Molecular Biology and Pharmacology, Washington University, St
Louis, MO 63110, USA.
Author for correspondence (e-mail:
jhebert{at}aecom.yu.edu)
Accepted 30 May 2006
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SUMMARY |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Key words: Basal ganglia, Ganglionic eminence, FGF, SHH, GLI3, Telencephalon, Patterning, Mouse
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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;
Campbell, 2003;
Zaki et al., 2003;
Hébert, 2005). For
example, in embryos mutant for Pax6 and Emx2, two genes
expressed in the dorsal telencephalon, precursor cells fail to adopt or
maintain a cortical fate and instead adopt, at least in part, the fate of
basal ganglia cells (Muzio et al.,
2002). Conversely, homeobox genes expressed in the ventral
telencephalon, such as Gsh2, Nkx2.1 and Dlx2, and the bHLH
gene Mash1 (Ascl1 - Mouse Genome Informatics) are essential
for proper specification of ventral fates
(Anderson et al., 1997;
Szucsik et al., 1997;
Casarosa et al., 1999;
Horton et al., 1999;
Sussel et al., 1999;
Corbin et al., 2000;
Toresson and Campbell, 2001;
Yun et al., 2003). Although
progress has been made in understanding how morphogens might restrict
expression of these genes to ventral or dorsal domains, many points remain
unclear (Hébert,
2005).
Sonic hedgehog (SHH) is a secreted factor that is required for the
induction of ventral cell types throughout the neural tube, including the
forebrain. In the telencephalon, loss of SHH signalling leads to a loss of
ventral cell types that normally express Dlx2, Gsh2 and
Nkx2.1, at the expense of dorsal cell types that express
Pax6 and Emx2 (Ericson
et al., 1995; Chiang et al.,
1996; Ohkubo et al.,
2002; Fuccillo et al.,
2004). Likewise, ectopic expression of the Shh gene can
induce expression of Dlx2 and Nkx2.1 in the dorsal
telencephalon of zebrafish and mice
(Ericson et al., 1995;
Barth and Wilson, 1995;
Hauptmann and Gerster, 1996;
Shimamura and Rubenstein,
1997; Kohtz et al.,
1998). In the spinal cord, SHH is thought to act directly on
neural precursor cells to induce ventral features
(Jessell, 2000;
Briscoe and Ericson, 2001).
Although SHH signalling is essential for telencephalic precursor cells to
adopt a ventral fate, it is not strictly necessary for this process. The
zinc-finger transcription factor gene Gli3 antagonizes Shh
and dorsalizes the telencephalon (Grove et
al., 1998; Theil et al.,
1999; Aoto et al.,
2002; Kuschel et al.,
2003; Rallu et al.,
2002). Remarkably, embryos mutant for both Shh and
Gli3 exhibit grossly normal dorsoventral patterning, implying that
other factors can pattern this axis of the telencephalon
(Aoto et al., 2002;
Rallu et al., 2002).
Candidates for the ventralizing signal are the fibroblast growth factors
(FGFs).
The anterior neural ridge at the anterior end of the neural plate forms the
rostral midline once the neural tube has closed. In mice, both the ridge and
rostral midline express several FGF genes, Fgf8, Fgf14, Fgf15, Fgf17
and Fgf18 (McWhirter et al.,
1997; Maruoka et al.,
1998; Xu et al.,
1999; Crossley et al.,
2001; Wang et al.,
2000). Three FGF receptor genes are widely expressed in neural
precursor cells, Fgfr1, Fgfr2 and Fgfr3
(Orr-Urtreger et al., 1991;
Peters et al., 1992;
Peters et al., 1993;
Hébert et al., 2003).
FGFs have been postulated to specify both dorsal and ventral cell types in the
telencephalon. In chick embryos, FGF signalling, following activation of the
Wnt pathway is required for inducing expression of dorsal features, such as
expression of the neocortical marker Emx1
(Gunhaga et al., 2003). In
zebrafish, FGF signalling is required for the ventral telencephalon to form.
The expression of markers for specific populations of ventral neurons is
diminished or absent in fgf8 mutants (Shanmugaligam et al., 2000).
When FGF signalling is further decreased by inhibition of the intracellular
signalling pathway or by knocking down fgf8 and fgf3
expression using morpholinos, ventral precursor cells expressing dlx2
or nk2.1b are reduced or absent
(Shinya et al., 2001;
Walshe and Mason, 2003). In
chick embryos, application of soluble FGFR4 leads to a loss of
Nkx2.1-expressing telencephalic cells
(Marklund et al., 2004).
Moreover, in mice, FGF8-soaked beads can induce expression of ventral markers
in dorsal telencephalic explants in culture
(Kuschel et al., 2003).
Whether FGF signalling is required in the embryonic mammalian telencephalon
for specifying either dorsal or ventral telencephalic cells remains unknown.
Moreover, how FGFs interact with other signalling molecules, such as SHH, is
unclear.
In this study, the role of FGF signalling in patterning the dorsoventral
axis of the telencephalon is examined. Using a conditional genetic approach in
the mouse, FGF signalling is disrupted specifically in the telencephalon at
the earliest stages of its development. All combinations of two receptors are
deleted and examined for patterning defects. Although
Fgfr2;Fgfr3 double mutants that retain only one functional
copy of Fgfr1 appear grossly normal, Fgfr1;Fgfr3
and Fgfr1;Fgfr2 mutants exhibit severe ventral phenotypes.
In the Fgfr1;Fgfr3 mutant, ventromedial precursor cells are
specified but fail to differentiate, whereas in the
Fgfr1;Fgfr2 mutant, precursor cells with ventral
characteristics fail to develop and cells all along the dorsoventral axis
adopt a dorsal fate. This occurs despite evidence of active SHH signalling.
Furthermore, although the Shh phenotype can be rescued by loss of
Gli3 expression (Rallu et al.,
2002), the Fgfr1;Fgfr2 phenotype cannot, placing
FGF signalling downstream of these genes in generating ventral cells.
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MATERIALS AND METHODS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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; Yamagushi et al., 1994;
Arman et al., 1998), therefore
floxed alleles of these genes were used to generate telencephalic specific
knockouts when crossed to Foxg1cre mice, as previously
described (Hébert et al.,
2003; Yu et al.,
2003). Fgfr1lox/+,
Fgfr1lox/+;Fgfr3null/+ and
Fgfr1lox/+;Fgfr2lox/+ carrying the
Foxg1cre allele do not exhibit the phenotypes described in
this study and were used as controls. The Fgfr3 allele used is a null
allele (Deng et al., 1996). As
Fgfr3 homozygous null mice are viable but breed poorly, heterozygotes
were used in the cross. Mutant embryos were obtained at the ages indicated in
the expected ratios with no signs of necrosis. A total of 19
Foxg1cre/+;Fgfr1lox/lox;Fgfr3null/null,
three
Foxg1cre/+;Fgfr2lox/lox;Fgfr3null/null
and 31
Foxg1cre/+;Fgfr1lox/lox;Fgfr2lox/lox
embryos were used and at least three embryos of each genotype were used for
each experiment. Mice carrying the Gli3-null (extra toes)
allele were obtained from Jackson Laboratories.
RNA is situ hybridization and immunohistochemistry
In situ hybridization was carried out according to two protocols: one using
radioactive RNA probes on sections and the other DIG labelled probes in whole
mount. For the radioactive in situ, frozen sections were prepared and
hybridized to 35S-labelled probes, as previously described
(Frantz et al., 1994). For the
in situ hybridization of whole-mount mouse embryos using digoxigenin-labelled
probes, the procedure was performed as described
(Henrique et al., 1995) with
the exception that BM purple (Roche) was used instead of NBT/BCIP to reveal
expression patterns. A minimum of three mutant and three control embryos were
analyzed for each probe (except for the E16.5 Fgfr1;Fgfr2 double
mutant in Fig. 4 for which only
one viable embryo was obtained and analysed). Immunohistochemistry for NPY was
performed as previously described (Marin
et al., 2000) with a 1:2500 dilution of polyclonal rabbit serum
(generous gift from S. A. Anderson).
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)
and precursor cells acquire ventral fates. Embryos were collected and frozen
in OCT. Fresh frozen sections were used for either BrdU staining, as
previously described (Hébert et
al., 2003), or for TUNEL analysis according to the manufacturer's
specifications (Roche, Catalogue # 2 156 792). Coronal sections for control
and mutants were matched so that they correspond to the same position along
the anteroposterior axis of the telencephalon. Sections were counterstained
with Syto11 (Molecular Probes). The fraction of BrdU or TUNEL-positive cells
is determined by counting the number of these cells in a radial segment
spanning from the ventricular surface to the outer edge of the neural tissue
and dividing by the total number of cells in the segment (segments contain
200 total cells). Segments used to count dorsal cells are at 45°
ventral to the dorsal midline and ventral segments are 45° dorsal to the
ventral midline. Midline segments are defined as an area encompassing 200
cells and obtained by drawing a line through the points were the telencephalic
hemispheres meet dorsally and ventrally. A 100 Syto11-positive cells are
counted on either side of these points to establish the 200-cell segment.
TUNEL- or BrdU-positive cells within this segment are then counted. At least
two segments from each of three separate embryos are counted in each case.
Cell cycle exit assay
Female mice carrying E10.5 embryos were injected with BrdU. Embryos were
collected at E11.5 and embedded in OCT. Cryosections (10 µm) were fixed (4%
paraformaldehyde), boiled in 10 mM sodium citrate for Ki67 antigen retrieval,
blocked (5% goat serum, 0.1% Triton X-100), incubated overnight at 4°C
with Ki67 antibody (1:100, Novocastra monoclonal), incubated 1 hour with
FITC-coupled secondary, post-fixed, treated with 2 N HCl, neutralized with 100
mM Na Borate, blocked, incubated with rat anti-BrdU (1:1,000, Oxford
Biotechnology), incubated with Texas Red-coupled anti-rat secondary and
counterstained with Hoechst 33342. Cells in sectors corresponding to the MGE
area were counted as described above for BrdU and TUNEL cell counts.
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RESULTS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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; Peters et al.,
1992; Peters et al.,
1993; McWhirter et al.,
1997; Maruoka et al.,
1998; Xu et al.,
1999; Wang et al.,
2000; Crossley et al.,
2001; Hébert et al.,
2003). In addition, the disruption of ligand gene expression can
have indirect effects on telencephalic precursors by affecting the development
of neighbouring ectodermal or mesodermal tissues. Fgfr1 and
Fgfr2 were deleted in the telencephalon using a Cre/loxP
approach to bypass the early embryonic lethality associated with wholeembryo
knockouts of these genes (Deng et al.,
1994; Yamaguchi et al.,
1994; Arman et al.,
1998). Loss of Fgfr3 or Fgfr2 on their own does
not lead to significant patterning defects (data not shown), whereas loss of
Fgfr1 in the telencephalon leads to an olfactory bulb defect
(Hébert et al., 2003).
In this study, all combinations of FGFR double mutants are generated using the
crosses depicted in Fig. 1A.
All three double mutant embryos were viable to at least E14.5. Except for the
lack of a nasal process and a smaller telencephalon in the
Fgfr1;Fgfr2 double mutant
(Fig. 1C), no gross
morphological defect could be identified upon observing whole E12.5
embryos. The loss of one copy of Foxg1 resulting from insertion of cre at this locus could in theory contribute to the defects observed with loss of FGFR genes described below. However, (1) as Foxg1 heterozygosity on its own does not lead to any patterning defect between E9.5 and E12.5, (2) as no genetic interaction is revealed between Foxg1 and FGFR genes even in the Foxg1cre/+;Fgfr1+/-;Fgfr2-/-;Fgfr3-/- mutant (Fig. 2B,F,J), and (3) as phenotypes analogous to the ones described here implicating FGF signalling in ventral telencephalic development have been obtained in other systems in which Foxg1 is wild type (see Discussion), it is unlikely that loss of one copy of Foxg1 contributes to the observed phenotypes.
One copy of Fgfr1 is largely sufficient for normal dorsoventral patterning
The telencephalon of E12.5 double mutant embryos was examined by RNA in
situ hybridization analysis using probes for Pax6 and Emx2
(dorsal markers), Dlx2 and Mash1 (ventral markers), and
Nkx2.1 (ventromedial marker). The Fgfr2;Fgfr3
mutant displayed grossly normal morphology at E12.5
(Fig. 2B,F,J). This mutant, in
addition to being deficient in Fgfr2 and Fgfr3, lacks one
copy of Fgfr1 (Fig.
1A). Despite this, normal patterns of Pax6, Dlx2 and
Nkx2.1 expression are observed
(Fig. 2B,F,J), indicating that
one copy of Fgfr1 is largely sufficient to pattern the dorsoventral
axis of the telencephalon. Owing to the lack of an obvious patterning defect
in this mutant, further analyses focused on the Fgfr1;Fgfr3
and Fgfr1;Fgfr2 mutants.
Generation of ventral telencephalic precursor cells requires FGF signalling
In the Fgfr1;Fgfr3 mutant, the dorsoventral borders of
Pax6, Dlx2, Nkx2.1 and Mash1 expression match those found in
control embryos (Fig. 2C,G,K
arrowheads; Fig. 4K),
suggesting that the specification of dorsal and ventral precursors has
occurred normally. However, the morphology of the ventral telencephalon in
this mutant is abnormal. No sulcus forms between areas where the medial and
lateral ganglionic eminences normally differentiate. In addition, the septum
is missing. This phenotype is also observed in the Fgfr1 single
mutant (Tole et al., 2006).
Loss of the normal ventral morphology, without loss of ventral precursor
cells, suggests that a process other than specification of ventral precursors,
such as cell differentiation or survival, is disrupted in the
Fgfr1;Fgfr3 mutant (addressed below).
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To assess whether the observed phenotypes might be due to changes in cell survival or proliferation, Fgfr1;Fgfr3 and Fgfr1;Fgfr2 mutants were analyzed using TUNEL and BrdU incorporation assays at E10.5, a stage when recombination of the floxed alleles in the mutant is complete and prior to the start of neurogenesis. Sections of telencephalons were partitioned into defined sectors that include dorsal, ventral and dorsomedial components (see Materials and methods). No difference in the percentage of cells incorporating BrdU or staining with TUNEL is observed in any sector between control and Fgfr1;Fgfr3 mutant embryos. However, statistically significant differences are observed between control and Fgfr1;Fgfr2 mutant embryos (Fig. 3A,B). Namely, slightly less proliferation is observed in the ventral telencephalon of this mutant compared with control (42.9±1.2% versus 48.8±2.1%, P=0.02) and an increase in apoptosis is observed in the dorsal midline of the mutant (21.3±2.6% versus 13.5±1.5%, P<0.0001). The reduced levels of ventral proliferation in the Fgfr1;Fgfr2 double mutant could in part explain the loss of ventral precursor cells.
Another possibility is that ventral precursor cells fail to be specified in the Fgfr1;Fgfr2 mutant. To address this point, we have analyzed the expression of the ventral telencephalic marker Nkx2.1 in the E9.25-9.75 mutant. Unlike other ventral markers, Nkx2.1 is readily detectable in control embryos at this age. In addition, at this age, expression of Nkx2.1 can be associated on a morphological basis with the telencephalon as opposed to the hypothalamus (or ventral diencephalon) where it is also expressed. Consistent with a role for FGF signalling in specifying ventral precursor cells, telencephalic, but not diencephalic, expression of Nkx2.1 is lost in the E9.25-E9.75 Fgfr1;Fgfr2 double mutant (Fig. 3C-F).
Differentiation of ventral telencephalic cells requires FGF signalling
In the Fgfr1;Fgfr3 mutant, the loss of the septum and of
the sulcus between the ganglionic eminences without a loss of ventral
precursor cells suggests that differentiation of ventral cell types in the
telencephalon is impaired. Therefore the expression of genes that mark
differentiating ventral cells was examined. Expression of Lhx6,
Lhx7 and Shh, which is normally found in the differentiating
field of the medial ganglionic eminence and septal areas, is almost absent in
the mutant (Fig. 4B,E and not
shown), whereas expression of Ebf1, which marks differentiating cells
of the lateral ganglionic eminence, is unaffected
(Fig. 4H). Together with the
TUNEL and BrdU results described above, this suggests that FGF signalling is
required to promote the differentiation, rather than the survival, of
ventromedial cell types. In the Fgfr1;Fgfr2 mutant, not only
is Lhx6, Lhx7 and Shh expression lost, but so is
Ebf1 (Fig. 4C,F,I), as
would be expected, given the loss of ventral precursor cells
(Fig. 2D,H,L).
In order to determine whether differentiation of ventral cell types was
affected in older FGFR mutant embryos, we examined the presence of ventral and
dorsal neurons at E16.5. Consistent with the early loss of all differentiated
ventral cell types in the Fgfr1;Fgfr2 mutant
(Fig. 4C,F,I), expression of a
ventral marker for GABAergic interneurons, Gad67, is lost in the
ventral telencephalon at the expense of the dorsal neuronal marker,
Tag1 (Fig. 4O,R,S).
However, in the Fgfr1;Fgfr3 mutant, the domains of
Gad67 and Tag1 expression are similar to those in controls
(Fig. 4M,N,P,Q), as might be
expected, as neurons derived from the LGE are still produced at earlier ages
(Fig. 4H). However, expression
of NPY, a marker for a subclass of migratory interneurons derived from
Nkx2.1-positive precursors in the MGE
(Marin et al., 2000;
Anderson et al., 2001), are
missing in the Fgfr1;Fgfr3 mutant at E18.5 (see Fig. S2 in the
supplementary material), consistent with the early loss of MGE-derived neurons
(Fig. 4B,E).
To address the nature of disrupted neurogenesis in the ventral medial area of the Fgfr1;Fgfr3 mutant, the expression of genes that normally mark the germinative layers of the MGE, the ventricular zone (VZ) and subventricular zone (SVZ), was examined. At E12.5, expression of Hes5 and Lhx2 normally marks the VZ, whereas Prox1 marks the SVZ. In the mutant, however, elevated levels of Prox1 expression are found in the VZ, coincident with apparent reductions in the levels of Hes5 and Lhx2 expression (Fig. 5A-C). This suggests that there is a loss of VZ precursor cells at the expense of SVZ precursors, which does not readily explain the loss of neurons.
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), and BrdU, which marks cells that had been cycling a
day before. The fraction of double-labelled (BrdU+Ki67) cells over total
BrdU-labelled cells is 66% in mutants compared with 25% in controls
(P<0.0001; Fig.
5D,E). This change is likely to be in large part responsible for
the lack of neurons observed in the Fgfr1;Fgfr3 mutant.
Shh and Gli1 remain expressed in the Fgfr1;Fgfr2 mutant
The loss of ventral precursor cells in the Fgfr1;Fgfr2
mutant mimics the phenotype observed in mice in which SHH signalling is
abolished in the telencephalon using a tissue-specific knockout of the
smoothened (Smo) gene (Fuccillo
et al., 2004). In the Smo mutant, Pax6
expression expands to the ventral midline, while telencephalic expression of
Nkx2.1 and Gsh2 are lost. Given these matching phenotypes,
the question arises as to whether FGF signalling acts either through or
independently of SHH to generate ventral cell types.
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), was
examined. Gli1 is expressed in Foxg1-positive telencephalic
cells in both the control and mutant at E10.5
(Fig. 6B,C), suggesting that
not only is SHH expressed, but that it is also active in the
Fgfr1;Fgfr2 mutant and that it is not sufficient to generate
ventral cell types. This indicates that SHH requires Fgfr1 and
Fgfr2 to generate ventral telencephalic cells and, consequently, that
FGF signalling acts independently or downstream of SHH. Consistent with these
results, Shh is required to maintain Fgf8 expression
(Ohkubo et al., 2002;
Aoto et al., 2002) and
FGF8-soaked beads can induce ventral gene expression in dorsal telencephalic
explants in culture, even when SHH signalling is inhibited
(Kuschel et al., 2003).
Loss of Gli3 does not rescue the Fgfr1;Fgfr2 phenotype
Shh and Gli3 act antagonistically to pattern the
dorsoventral axis of the telencephalon
(Rallu et al., 2002). In the
Shh mutant, ventral cell types are lost and dorsal ones expand, and
the opposite is observed in the Gli3 mutant - ventral cell types
expand and dorsal ones are lost. However, grossly normal dorsoventral
patterning is restored in mutants that lack both copies of Shh and
one or both copies of Gli3 (Aoto
et al., 2002; Rallu et al.,
2002). Can Gli3 also rescue the loss of ventral cell
types in the Fgfr1;Fgfr2 mutant?
This question was addressed by analyzing Fgfr1;Fgfr2
mutants that carry one or two mutant alleles of Gli3. In these
mutants, loss of Gli3 does not rescue the loss of ventral cell types.
In the Fgfr1;Fgfr2 mutant that carries just one mutant copy
of Gli3, Pax6 and Emx2 expression extends to the
ventral-most area of the telencephalon and Dlx2 expression is largely
or completely lost as it is in the Fgfr1;Fgfr2 double mutant
(Fig. 7E-M). The ventromedial
area that is devoid of Pax6 and Emx2 expression but positive
for Dlx2 expression in the mutants is likely to coincide with the
anteroventral hypothalamus, as revealed in serial sections by reduced or
absent Foxg1 expression (not shown). The failure of one mutant copy
of Gli3 to rescue the Fgfr1;Fgfr2 phenotype, in
contrast to its ability to rescue the Shh phenotype
(Rallu et al., 2002),
indicates that FGF signalling acts downstream of Gli3 and
Shh.
In the Fgfr1;Fgfr2 mutant that carries two mutant copies
of Gli3, the loss of ventral precursor cells is also not rescued.
However, in this case development of the telencephalon is greatly compromised
(Fig. 7A-D). Unlike the
Shh;Gli3 double homozygous mutant
(Rallu et al., 2002), the
Fgfr1;Fgfr2;Gli3 triple homozygous mutant does not
exhibit a high frequency of exencephaly (less than 20%), but rather a
flattening and significant reduction in the size of the telencephalon
(Fig. 7D). Nevertheless, in
Foxg1-positive areas, Pax6 and Emx2, but not
Dlx2, are expressed (Fig.
7N-P; see Fig. S3 in the supplementary material), suggesting that
complete loss of Gli3 does not rescue the loss of ventral cells
observed in the Fgfr1;Fgfr2 mutant and that FGF signalling
in fact acts downstream of Gli3. Consistent with previous reports
indicating that Gli3 is required for the cortical hem to form
(Grove et al., 1998),
expression of Wnt3a and Wnt2b, markers for the hem, are
absent in the
Fgfr1-/-;Fgfr2-/-;Gli3-/- mutant
(Fig. 7T-U and not shown), but
present in the Fgfr1-/-;Fgfr2-/- and
Fgfr1-/-;Fgfr2-/-;Gli3+/- mutants
(Fig. 7Q-S and not shown).
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DISCUSSION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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). The
same phenotype is also obtained in embryos in which Fgf8 is deleted
(Storm et al., 2006).
Therefore, both SHH and FGF signalling are similarly required for generating
ventral precursors. In this process, FGFs could be acting upstream, downstream
or in parallel to SHH signalling.
FGFs act downstream of SHH
Previous evidence supports a model in which FGFs act downstream of
Shh to generate ventral cell types
(Fig. 8). First, although SHH
is required to induce ventral telencephalic cell types
(Ericson et al., 1995;
Chiang et al., 1996;
Ohkubo et al., 2002;
Fuccillo et al., 2004),
ventral cells can still develop if both SHH and GLI3 are lost, indicating that
another factor can generate ventral cells independent of SHH
(Aoto et al., 2002;
Rallu et al., 2002). Second,
the maintenance of Fgf8 expression requires Shh
(Aoto et al., 2002;
Ohkubo et al., 2002). Third,
FGF8-soaked beads can induce expression of ventral markers and repress
expression of dorsal ones when placed on cultured explants of dorsal
telencephalon, even when SHH signalling is inhibited with cyclopamine
(Kuschel et al., 2003). And
finally, zebrafish embryos that lack Fgf8 or are treated with
morpholinos against Fgf8 and Fgf3 show loss of ventral cell
types (Shanmugalingam et al.,
2000; Shinya et al.,
2001; Walshe and Mason,
2003) and chick embryos treated with soluble FGFR4 show a loss of
Nkx2.1 expression (Marklund et
al., 2004). However, direct genetic evidence in mammals
demonstrating a role for FGFs in generating ventral telencephalic cell types
has been lacking.
Three results described in this study establish that FGFs in fact act
downstream of Shh and Gli3. First, Shh expression
is not affected in the Fgfr1;Fgfr2 mutant
(Fig. 6). This is also the case
with loss of Fgf8, whereby Shh expression is maintained
(Kawauchi et al., 2005).
Second, Gli1 expression, which is dependent on SHH activity
(Bai et al., 2002), is
maintained in the Fgfr1;Fgfr2 mutant
(Fig. 6), indicating that SHH
activity is not sufficient to generate ventral cells and depends on FGF
signalling. And finally, although loss of Gli3 rescues the lack of
ventral precursors in the Shh mutant
(Rallu et al., 2002), it does
not do so in the Fgfr1;Fgfr2 mutant
(Fig. 7; see Fig. S3 in the
supplementary material), placing FGF signalling downstream of Shh and
Gli3.
The question remains as to whether FGF signalling, acting downstream of SHH
to generate ventral telencephalic cells, directly specifies these cells or
whether it is required to promote their proliferation or survival once they
have already been specified. Several lines of evidence suggest that FGF
signalling does in fact induce or specify ventral cells. First, FGF8-soaked
beads can ectopically induce ventral telencephalic cells
(Kuschel et al., 2003).
Second, even at early stages of telencephalon development, ventral
telencephalic cells that normally express Nkx2.1 are not present in
the Fgfr1;Fgfr2 or Fgf8 mutants
(Fig. 3)
(Storm et al., 2006),
consistent with a role for FGF signalling in specifying ventral cells. This
does not exclude the possibility that FGF signalling also promotes the
proliferation and survival of ventral precursor cells. In fact, reduced
proliferation in the ventral telencephalon is observed in the
Fgfr1;Fgfr2 mutant at E10.5
(Fig. 3A) and both reduced
proliferation and increased apoptosis are observed in the Fgf8 mutant
as early as E9 (Storm et al.,
2006).
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;
Rallu et al., 2002),
presumably owing to FGF signalling. But how can FGFs generate ventral cells if
Shh is required to maintain expression of FGF genes, in particular
Fgf8 (Ohkubo et al.,
2002)? The likely answer is that FGF gene expression is normally
repressed by Gli3 (Fig.
8). In the Shh mutant, Fgf8 expression is lost
because of unchecked repression by Gli3, but in the
Shh;Gli3 double mutant, Fgf8 is no longer repressed
by Gli3. Consistent with Gli3 repressing FGF gene
expression, Fgf8 expression expands in the Gli3 mutant
(Theil et al., 1999;
Aoto et al., 2002;
Kuschel et al., 2003).
Furthermore, in the Shh;Gli3 double mutant, Fgf8
expression also expands (Aoto et al.,
2002), suggesting that Shh promotes Fgf8
expression only indirectly by repressing Gli3
(Fig. 8).
Whether similar interactions between Gli3, Shh, and FGF signalling
occur in other parts of the developing CNS remains unclear. Interestingly,
loss of Gli3 can also rescue loss of SHH signalling in the spinal
cord. In Shh;Gli3 or Smo;Gli3 double
mutants, ventral neuron generation is rescued as is dorsoventral patterning,
indicating that other yet to be identified factors pattern the spinal cord
(Litingtung and Chiang, 2000;
Persson et al., 2002;
Wijgerde et al., 2002). Given
the results presented here and that FGF genes are expressed within or
immediately adjacent to the spinal cord
(Crossley and Martin, 1995;
Borja et al., 1996;
Maruoka et al., 1998;
Xu et al., 1999), FGFs become
excellent candidates for factors that generate ventral cell types in the
spinal cord. It should be noted that at least in the spinal cord, but perhaps
also in the telencephalon, loss of Gli3 does not completely rescue
the loss of Shh phenotype
(Litingtung and Chiang, 2000;
Persson et al., 2002;
Wijgerde et al., 2002),
suggesting that SHH has a role in patterning neural tissue that goes beyond
inactivating GLI3.
The nature of the signals that dorsalize the telencephalic cells in the
Fgfr1;Fgfr2;Gli3 triple mutant remain unclear. Previous evidence has
suggested that FGF signalling in combination with Wnt signalling dorsalizes
telencephalic precursor cells (Gunhaga et
al., 2003). It is possible that in the Fgfr1;Fgfr2;Gli3
mutant, the remaining FGF signalling through FGFR3 along with a Wnt that is
expressed beyond the cortical hem area (such as Wnt7a)
(Grove et al., 1998) accounts
for the dorsalization of the remaining telencephalon.
FGFR1 is the likely receptor for FGF8 in the early telencephalon
Of the three FGF receptor genes expressed in telencephalic precursor cells,
Fgfr1 plays a dominant role. Telencephalons that are deficient for
both copies of Fgfr2 and Fgfr3 but that retain only one copy
of Fgfr1 exhibit grossly normal patterning
(Fig. 2), indicating that FGFR1
produced from one allele is sufficient to transmit most of the FGF signalling
load. Conversely, although loss of Fgfr2 or Fgfr3 on their
own have little or no patterning defect in the telencephalon, loss of
Fgfr1 alone results in an olfactory bulb defect
(Hébert et al., 2003),
a loss of midline glia, cerebral commissures and differentiated ventromedial
cell types (Tole et al.,
2006), indicating that Fgfr1 on its own is necessary for
telencephalic development. The Fgfr1 and
Fgfr1;Fgfr3 phenotypes are similar, as are the
Fgfr2 and Fgfr2;Fgfr3 phenotypes
(Fig. 2; G.G., S.K.M. and
J.M.H., unpublished), suggesting that Fgfr3 does not play a
significant role in the patterning processes described in this study. The key
roles played by Fgfr1 are likely to be conserved across species. In
humans, reduction or loss of expression of this gene leads to Kallmann
syndrome, which includes olfactory bulb and commissural defects
(Dode et al., 2003).
Reduction or loss of Fgf8 expression leads to comparable
phenotypes to those obtained with loss of Fgfr1. In zebrafish,
ventral, midline and commissural defects are observed when fgf8
expression is lost or reduced
(Shanmugalingam et al., 2000;
Shinya et al., 2001;
Walshe and Mason, 2003). Mouse
embryos in which Fgf8 is hypomorphic can lack olfactory bulbs
(Meyers et al., 1998) and
those in which Fgf8 is null lack ventral precursor cells
(Storm et al., 2006). However,
in the latter case the phenotype is more similar to the
Fgfr1;Fgfr2 phenotype described here, suggesting that FGF8
acts not only through FGFR1, but also through FGFR2. Given the similarities in
the phenotypes obtained to date with reductions or loss of Fgf8 and
with the different FGFR mutants, it is likely that in the early telencephalon
FGF8 acts primarily through FGFR1 and secondarily through FGFR2.
This is surprising, given previous studies suggesting that FGF8 has little
or no affinity for FGFR1 in cell mitogenicity and binding assays, and that
FGFR3 is the highest affinity receptor for this ligand
(Ornitz et al., 1996;
Chellaiah et al., 1999). This
discrepancy could potentially be explained by the presence of alternatively
spliced variants of the Fgfr3 transcript in the different cell types
or the differential expression of unidentified co-factors. Nevertheless,
whether Fgfr3 in any way compensates for loss of Fgfr1
and/or Fgfr2 in the early telencephalon awaits analysis of the triple
FGFR mutant.
|
;
Maruoka et al., 1998;
Xu et al., 1999;
Wang et al., 2000),
Fgf7 is expressed in the lateral telencephalon
(Mason et al., 1994),
Fgf1 and Fgf2 are believed to be widely expressed throughout
the telencephalic neuroepithelium (e.g.
Dono et al., 1998), and other
FGF genes for which the telencephalic expression pattern in mice has not yet
been characterized may also be expressed. Of note, Fgf19 plays a role
in zebrafish in promoting ventral forebrain development
(Miyake et al., 2005), but its
expression or role in the mouse is unknown. Although in this study no role was
uncovered for Fgfr3 in generating ventral cell types, this gene is
required for regulating the onset of oligodendrocyte terminal differentiation
that occurs postnatally (Oh et al.,
2003). Given that the expression of FGF ligands is poorly
characterized postnatally, and that mutations in FGF ligand genes have not yet
revealed a similar oligodendrocyte differentiation phenotype, it remains
unclear which ligands are likely to interact with FGFR3.
A model for the formation of the telencephalic midline
Holoprosencephaly, the incomplete separation of the telencephalic
hemispheres, is the most common developmental forebrain defect in humans
(Muenke and Beachy, 2001).
Although mutations in the SHH pathway are known to cause holoprosencephaly in
both humans and mice, it remains a mystery how the absence of Shh
expression, which is normally present only ventrally, can result in not only
the loss of ventral cells but also loss of the rostral and dorsal midline
(Hayhurst and McConnell,
2003). FGF signalling in the telencephalon is also likely to be
required for midline formation. The Fgfr1;Fgfr3 mutant lacks
rostral midline glial cell types, the indusium griseum and midline zipper
glia, and all three cerebral commissures
(Tole et al., 2006); and the
Fgfr1;Fgfr2 and Fgf8 mutants have a higher rate of
apoptosis (Fig. 3B)
(Storm et al., 2006) and a
wider domain of Bmp4 expression in the dorsal midline (data not
shown) (Storm et al., 2003),
indicating that FGFs regulate formation of the rostrodorsal midline.
Consistent with a role for FGF signalling in midline formation, in
zebrafish, loss of FGF activity also leads to disruption of the midline and
severe commissural axon pathway defects
(Shanmugalingam et al., 2000;
Walshe and Mason, 2003).
Furthermore, the level of Fgf8 expression appears to regulate dorsal
midline formation by regulating Bmp4 expression
(Storm et al., 2003); and
ectopic FGF8 can induce structures resembling a dorsal midline
(Crossley et al., 2001).
Gli3 is also required for promoting the expression of BMP and WNT
genes and for forming the dorsal midline
(Grove et al., 1998;
Theil et al., 1999;
Kuschel et al., 2003).
Therefore Gli3 and FGF signalling are likely to interact in
regulating formation of the dorsal midline
(Fig. 8). These previous
reports, along with the results presented here, point to a model whereby SHH
promotes ventral and midline development indirectly by regulating GLI3 and FGF
signalling.
|
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ACKNOWLEDGMENTS |
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|
Footnotes |
|---|
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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