1 Umeå Center for Molecular Medicine, Building 6M, 4th floor, Umeå
University, S-901 87 Umeå, Sweden
2 Department of Biochemical Pharmacology, Bristol-Myers Squibb Pharmaceutical
Research Institute, Buffalo, NY 14213, USA
3 Howard Hughes Medical Institute, Department of Biochemistry and Molecular
Biophysics, Columbia University, New York, NY 10032, USA
* Author for correspondence (e-mail: thomas.edlund{at}molbiol.umu.se)
Accepted 9 June 2004
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SUMMARY |
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Key words: Chick, Mouse, Retinoic acid
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Introduction |
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The assignment of an initial regional identity to neural progenitor cells
in the prospective telencephalon is an important step in the generation of the
functional subdivisions within the telencephalon. The cerebral cortex derives
from the dorsal region and the pallidum from the ventralmost region of the
early developing telencephalon. In mammals, the intermediate region of the
telencephalon contains neural progenitor cells of at least three different
structures: the striatum, the olfactory bulb and parts of the amygdala
(Campbell, 2003;
Deacon et al., 1994
;
Olsson et al., 1998
;
Schuurmans and Guillemot,
2002
). Studies in diverse vertebrate organisms have provided
evidence that patterns of expression of transcription factors early in
development delineate the future functional subdivisions of the telencephalon
along its DV axis, and that these expression patterns are largely conserved
among vertebrate embryos (Cobos et al.,
2001a
; Cobos et al.,
2001b
; Fernandez et al.,
1998
; Puelles et al.,
2000
; Puelles et al.,
1999
). Thus, examination of when and how these profiles of gene
expression are established in the telencephalon may reveal how telencephalic
cells acquire their early dorsal, intermediate and ventral characters.
The diverse and interdependent functions of patterning signals of the HH,
WNT, BMP, FGF and retinoid classes during forebrain and craniofacial
development have made it difficult to establish the precise role(s) of
individual signals in the early development of the telencephalon, and to
resolve whether these signals act directly on neural cells or indirectly on
surrounding tissues. In chick embryos, prospective neural tissue can be
separated from adjacent tissues at stages when forebrain cells normally
acquire dorsoventral DV regional character
(Cobos et al., 2001b;
Couly and Le Douarin, 1987
).
Thus, the stage at which telencephalic cells acquire different DV characters
can be defined, and the direct response of neural cells to putative inductive
signals and their mode(s) of action can be elucidated. Studies in chick have
provided evidence that anterior forebrain cells are specified as cells of
ventral character in response to an early phase of SHH signalling that
operates at gastrula stages (Gunhaga et
al., 2000
). More recent evidence suggests that at the neural fold
stage, WNT signals block ventral character and induce early dorsal character
in telencephalic cells (Gunhaga et al.,
2003
). Later, at the early neural tube stage, FGF signals derived
from dorsal midline cells act together with WNT signals to induce definitive
dorsal/precortical character in early dorsal cells
(Gunhaga et al., 2003
).
Collectively, these studies have provided information on the time at which
telencephalic cells acquire ventral and dorsal character, and the molecular
nature of some of the signalling molecules involved in these processes.
Although, they have failed to account for the patterning events that specify
telencephalic progenitor cells of an intermediate character. Emerging evidence
in mouse indicates that cells characteristic of the intermediate region of the
telencephalon are generated in Shh mutants
(Rallu et al., 2002b
) (H.
Toresson, PhD thesis, Lund University, 2001), but WNTs, BMPs and FGFs have not
been implicated directly in the specification of cells of intermediate
character (Rallu et al.,
2002a
). Thus, additional signals that act in concert with these
peptide growth factors are likely to participate in the induction of cells of
an intermediate telencephalic character.
Over the past few years, several lines of evidence have indicated that
retinoic acid (RA) signalling has an important role in patterning vertebrate
neural progenitors, and in neuronal specification
(Appel and Eisen, 2003;
Diez del Corral et al., 2003
;
Halilagic et al., 2003
;
Maden, 2001
;
Maden et al., 1998
;
Muhr et al., 1997
;
Novitch et al., 2003
;
Pierani et al., 1999
;
Schneider et al., 2001
). In
the developing spinal cord, recent findings have lead to a model in which RA
signalling establishes the intermediate region of the caudal neural tube, in
part by opposing the influence of FGF signalling
(Diez del Corral et al., 2003
;
Novitch et al., 2003
). The
fact that RA acts in a coordinated manner with WNT, FGF, BMP and SHH signals
to impose DV cell pattern in the spinal cord raises the possibility that RA
signalling also contributes to the developmental steps that specify
intermediate cell character in the telencephalon. There are several potential
sources of RA within or adjacent to the early developing telencephalon
(Blentic et al., 2003
;
Mic et al., 2002
), and there
is evidence that RA signalling influences anterior forebrain development
(Anchan et al., 1997
;
Halilagic et al., 2003
;
Schneider et al., 2001
;
Smith et al., 2001
;
Swindell et al., 1999
;
Toresson et al., 1999
;
Whitesides et al., 1998
) (H.
Toresson, PhD thesis, Lund University, 2001). The attenuation of RA signalling
at early stages of development led to aberrant expression of BMP and SHH
signals in ventral midline neural tube cells and in the prechordal plate
mesoderm that underlies the anterior neural plate; it also led to impaired
survival of head mesenchyme and ventral telencephalic cells
(Halilagic et al., 2003
). At
early neural tube stages, the gene encoding the RA synthetic enzyme
retinaldehyde dehydrogenase 3 (RALDH3) is expressed in the head ectoderm
adjacent to the early developing telencephalon
(Blentic et al., 2003
), and
inhibition of RA signalling at these stages results in a general perturbation
of the growth and development of the forebrain and frontonasal processes
(Anchan et al., 1997
;
Schneider et al., 2001
;
Whitesides et al., 1998
).
Thus, RA is required for the growth, patterning and survival of multiple
tissues of the early developing rostral head. At later stages of telencephalic
development, radial glial cells in the prospective striatum serve as a
localised source of retinoids, and retinoid signalling appears to enhance
neuronal differentiation in the striatum (H. Toresson, PhD thesis, Lund
University, 2001) (Toresson et al.,
1999
). However, from these studies it has remained unclear whether
RA signalling contributes to the initial specification of telencephalic
progenitor cells of intermediate character, rather than solely to later
aspects of cell differentiation, and if so whether RA acts directly on neural
cells or indirectly on adjacent tissues.
Using assays of neural differentiation in chick neural tissue, in vitro and in intact chick embryos, we provide evidence that RA signalling has a crucial role in specifying telencephalic cells of intermediate character. Our data also support the idea that FGF signalling maintains ventral progenitor character, in part, by opposing the influence of RA signals. Thus, the opponent roles of RA and FGF signals in establishing an intermediate positional character of neural cells appears to be conserved along the anteroposterior axis of the neural tube.
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Materials and methods |
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Mouse recombinant soluble FGFR4 (R&D Systems) was used at 150 nM
together with 0.5 µg/ml heparin (Sigma). FGF8 (R&D Systems) was used at
5 nM. Soluble WNT3A, mouse frizzled receptor 8 protein (mFrz8CRD-IgG) and
control condition media were generated as described
(Gunhaga et al., 2003).
All-trans retinoic acid (Sigma) and BMS189453
(Chen et al., 1995
;
Schulze et al., 2001
) were
used at 100 nM. Cyclopamine (Incardona et
al., 1998
) was used at 1 µM. BMP4 (R&D Systems) was used at
3 nM.
Whole-embryo culture
New culture method was essentially carried out as previously described
(Chapman et al., 2001). Heparin
acrylic beads (Sigma) were soaked in PBS (control) or mouse recombinant FGFR4
(R&D Systems). AG 1-X2 resin converted to formate form were soaked in DMSO
(control), all-trans retinoic acid (1 mM) or the synthetic retinoid BMS-189453
(Chen et al., 1995
;
Schulze et al., 2001
) (4 mM).
The beads were inserted into the prospective prosencephalon of HH stage 10-11
chick embryos and placed in contact with the neural ectoderm. The embryos were
maintained in New culture for
48 hours.
Cloning of chick Meis2 and generation of MEIS2 and EMX1 antiserum
A cDNA fragment corresponding to nucleotides 246-748 of the chick
Meis2 sequence (GenBank Accession Number AF199011) was obtained by
RT-PCR using total RNA isolated from E5 chick embryos as template and the
following oligonucleotide primers 5'-AAGGATGCGATCTACGG-3' and
3'-CTAAACCATCCCCTTGCT-5'.
The synthetic peptide (NH2) - MAQRYDELPHYGGMDGC - (COOH) was used to generate a rabbit anti-MEIS2 antibody. Rabbit anti-EMX1 was generated using a mix of (NH2-) CLATKQSSGEDIDVTSND (-COOH) and (Ac-) AGSEVSQESLLLHGC (-COOH) (Agrisera AB).
In situ hybridisation and immunohistochemistry
In situ RNA hybridisation histochemistry using chick digoxigenin-labelled
Meis2 probe was performed essentially as described
(Gunhaga et al., 2003).
Whole-mount in situ RNA hybridisation using chick digoxigenin-labelled
Raldh3 probe was performed as described
(Wilkinson and Nieto,
1993
).
For staining with the anti-EMX1, anti-NKX2.1 (BIOPAT immunotechnologies),
anti-MEIS2 and anti-cleaved caspase 3 (Cell Signaling) rabbit antibodies and
with the monoclonal anti-PAX6, anti-TTF1 antibodies (AbCam), embryos and
explants were fixed as described (Gunhaga
et al., 2003). To quantify the percentage of antigen-expressing
cells, each explant was serially sectioned at 8 µm, stained and counted,
the total numbers of cells were determined by counting the number of nuclei
using DAPI (Boehringer Mannheim).
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Results |
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|
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The generation of PAX6+ cells in stage 10 I explants indicates that prospective intermediate cells are exposed to early WNT signals. Consistent with this idea, in the presence of mouse frizzled receptor 8 protein (mFrz8CRD-IgG), an antagonist of WNT signals, the generation of PAX6+ cells (4±2% compared to 23±4% in untreated 14 I explants, P<0.01) was suppressed in stage 14 I explants, but MEIS2+ cells (20±5%) were still generated, and no EMX1+ or NKX2.1+ cells appeared (Fig. 2F). However, WNT3A exposure blocked the generation of MEIS2+ cells, increased the number of PAX6+ cells, and induced EMX1+ (25±5% compared with 0% in untreated stage 14 I explants, P<0.01) cells - a profile characteristic of the dorsal telencephalon (Fig. 2E). Thus, early WNT signalling appears to contribute to the induction of PAX6+ cells characteristic of the dorsal domain of the intermediate region, whereas high levels of WNT signals block intermediate and induce dorsal character in telencephalic cells.
RA is required and sufficient to induce cells of intermediate character
We next addressed the molecular nature of signal(s) that induce
intermediate character in telencephalic cells. RA acts as an activator of
MEIS1 and MEIS2 expression in the proximal region of the developing limb bud
(Mercader et al., 2000) and
MEIS2 was originally identified as a retinoid-inducible gene in P19 carcinoma
cells (Oulad-Abdelghani et al.,
1997
), raising the possibility that RA signals contribute to the
induction of MEIS2+ cells of intermediate character in the
developing telencephalon. Consistent with this possibility, the gene encoding
the RA synthetic enzyme RALDH3 starts to be expressed in the head ectoderm
adjacent to the rostral forebrain at
stage 9/10
(Blentic et al., 2003
), and by
stage 14, the Raldh3-expressing domain is located adjacent to the
ventral and intermediate regions of the telencephalon
(Fig. 3A). Thus, telencephalic
cells appear to be exposed to RA signals at the time they begin to acquire
intermediate character. To examine whether RA signalling is required for the
specification of cells of an intermediate character, we exposed stage 14 I
explants to the RAR antagonist BMS-1895453 (BMS453) (100 nM)
(Chen et al., 1995
;
Schulze et al., 2001
). Under
these conditions, the generation of MEIS2+ cells was blocked (0%
compared with 22±6% in untreated stage 14 I explants,
P<0.01), the number of PAX6+ cells (7±3%) was
reduced, and a small number of NKX2.1+ cells (5±3%) also
appeared, but the growth of the explants was not affected
(Fig. 3B). Thus, these results
provide evidence that RA signalling is required for the specification of cells
of intermediate character.
|
|
|
To examine whether FGF8 maintains ventral telencephalic character by suppressing RA signalling, we isolated V explants from stage 8 and 10 embryos, before and after the onset of Raldh3 expression in the adjacent head ectoderm, and exposed them to soluble FGFR4 (6 µg/ml), an inhibitor of FGF8 signalling. Under these conditions, soluble FGFR4 did not block the generation of NKX2.1+ cells, or induce MEIS2+ cells in stage 8 V explants (data not shown). By contrast, in stage 10 V explants, soluble FGFR4 blocked the generation of NKX2.1+ cells and induced a large number of PAX6+ (56±5%) and MEIS2+ (62±3%) cells (Fig. 6B) - a profile indicative of the intermediate region of the telencephalon, but did not suppress the growth of the explants. The changes in numbers of cells expressing NKX2.1, MEIS2 and PAX6 was significant (P<0.01) compared with the untreated stage 10 V explants. Thus, these results support the idea that that FGF8 blocks RA signalling in ventral telencephalic cells. We also tested whether FGF8 blocked the ability of RA to induce intermediate character in dorsal telencephalic cells by exposure of stage 8 D explants to RA (100 nM) and FGF8 (5 nM). Under these conditions, FGF8 blocked the ability of RA to induce MEIS2+ (0% compared to 82±4% in stage 8 D explants only exposed to RA, P<0.01) and ISL1+ neurons, but PAX6+ (63±5%) cells were still generated (Fig. 4B). Collectively, these results provide evidence that FGF signals maintain cells of ventral character in the telencephalon by blocking the ability of RA to induce intermediate character in ventral telencephalic cells.
|
|
FGF maintains telencephalic cells of ventral character in intact embryos
We also used New Culture methods
(Chapman et al., 2001) to
examine whether FGF activity maintains ventral and suppresses intermediate
telencephalic character in intact chick embryos. Control beads or beads soaked
in soluble FGFR4 were implanted into the ventral region of the anterior
prosencephalon of stages 9-10 embryos, and permitted to develop to stages
20-22. All embryos grafted with control beads (n=10) showed normal
morphology and dorsoventral patterning of the telencephalon
(Fig. 6C). In embryos grafted
with soluble FGFR4 beads (n=10), cells in the telencephalon failed to
express NKX2.1 and (as expected) EMX1, and in four embryos, ventral cells
ectopically expressed Meis2 (Fig.
6D). All embryos also had smaller heads and telencephalic vesicles
(Fig. 6C), with increased
numbers of cells that expressed cleaved caspase 3 predominantly in the more
dorsal regions of the telencephalon (see Fig. S1 at
http://dev.biologists.org/supplemental).
Thus, attenuation of FGF signalling does not lead to selective death or block
of proliferation of ventral telencephalic cells. These results provide
evidence that in intact chick embryos FGF activity maintains ventral and
suppresses intermediate telencephalic character by inhibiting cells to respond
to RA signalling.
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Discussion |
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To address these issues, we have established explant assays of neural
differentiation in chick embryos, and previous studies have provided evidence
that SHH signalling induces ventral character, and that WNT and FGF signals
act sequentially to induce dorsal/precortical character in telencephalic cells
(Gunhaga et al., 2000;
Gunhaga et al., 2003
). These
studies have so far failed to identify the signal(s) that induces intermediate
character in telencephalic cells. Our findings provide evidence that RA
signalling in neural cells is required and sufficient to induce cells of
intermediate character, and suggest that FGF signals maintain ventral
character by opposing RA signalling in ventral telencephalic cells.
Taken together with previous findings
(Campbell, 2003;
Gunhaga et al., 2000
;
Gunhaga et al., 2003
;
Rallu et al., 2002a
;
Schuurmans and Guillemot,
2002
), our results provide insights into the sequential steps
involved in assigning an initial DV regional identity to telencephalic neural
progenitor cells (Fig. 8). The
following model emerges from these findings. At gastrula stages, most or all
prospective telencephalic cells become specified as ventral
(NKX2.1+) cells in response to node-derived SHH signals
(Gunhaga et al., 2000
). At
neural fold and early neural plate stages, cells in the prospective dorsal and
intermediate regions of the telencephalon cells are exposed to WNT signals
that induce PAX6+ cells
(Gunhaga et al., 2003
). The
head ectoderm adjacent to the telencephalon then starts to express
Raldh3 (Blentic et al.,
2003
), exposing telencephalic cells to RA signals that promotes
the generation of intermediate (MEIS2+) cells. From the neural
plate stage, prospective ventral telencephalic cells are exposed to FGF8
derived from the anterior neural ridge
(Crossley et al., 2001
), and
FGF8 maintains ventral telencephalic character by opposing the influence of RA
signals in ventral cells. At early neural tube stages, the domain of
Fgf8 expression expands dorsally and FGF signals derived from the
dorsal midline region induce definitive dorsal/precortical (EMX1+)
cells (Gunhaga et al., 2003
),
and cells that are exposed to RA and low levels of FGF8 acquire intermediate
character.
|
FGF signalling appears to maintain ventral character in telencephalic cells
(Shinya et al., 2001;
Walshe and Mason, 2003
),
providing a potential explanation for the transient requirement for SHH in the
generation of ventral cells in the telencephalon
(Gunhaga et al., 2000
). Our
results extend these findings by showing that that FGF signalling also
maintains ventral progenitor character by suppressing the RA-mediated
induction of intermediate character in ventral cells. The opponent activities
of RA and FGF signals also has a parallel in the developing spinal cord, where
RA promotes and FGF suppress the expression of class I HD proteins
(Diez del Corral et al., 2003
;
Gunhaga et al., 2000
;
Novitch et al., 2003
). Thus,
in addition to the conserved function of SHH in inducing ventral progenitor
cells (Briscoe and Ericson,
2001
; Ericson et al.,
1995
), RA and FGF signals appear to have similar opponent roles in
establishing intermediate character at different levels of the developing
neural tube.
Finally, our results, together with previous studies, indicate that RA
signalling has important roles at several sequential stages in the generation
of striatal neurons. At gastrula stages, RA signalling appears to refine the
rostrocaudal identity of the anterior neural plate by modulating signalling
involved in axial mesoderm specification
(Halilagic et al., 2003). As
shown in this study, during the initial DV patterning of neural progenitor
cells in the telencephalon, RA signalling induces intermediate cells. At later
stages of telencephalic development, glial cells in the developing striatum
start to express Raldh3 (Smith et
al., 2001
), and serve as a localized source of retinoids (H.
Toresson, PhD thesis, Lund University, 2001)
(Toresson et al., 1999
), which
appear to enhance neuronal differentiation in the striatum (H. Toresson, PhD
thesis, Lund University, 2001) (Toresson
et al., 1999
).
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ACKNOWLEDGMENTS |
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Footnotes |
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