Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
* Author for correspondence (e-mail: dale{at}tx.technion.ac.il)
Accepted 6 October 2003
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SUMMARY |
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Key words: Xenopus laevis, XMeis3, Neural caudalization, Hindbrain-inducing center
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Introduction |
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Meis proteins form transcriptional complexes by forming dimeric or trimeric
DNA-binding complexes with Pbx and or Hox proteins
(Shen et al., 1998;
Jacobs et al., 1999
; Shanmugan
et al., 2000; Vlachakis et al.,
2000
). Through the formation of different complexes, Pbx/Meis
protein partners can modify the transcriptional activity of a specific Hox
protein in a given cell type. In flies, Meis/HTH is required for the nuclear
localization and subsequent DNA binding activity of Pbx/EXD
(Rieckhof et al., 1997
;
Kurant et al., 1998
); however,
in vertebrates, Meis proteins might not be required for nuclear localization
of Pbx proteins (Kilstrup-Nielsen et al.,
2003
). Work in Xenopus and Drosophila embryos
suggests that Meis proteins act as part of transcriptional activator complexes
(Dibner et al., 2001
;
Inbal et al., 2001
). Thus,
although Meis proteins may act as nuclear transporters and Hox co-factors,
they might actually possess intrinsic transcriptional activator function.
In Xenopus, the central nervous system (CNS) is induced in
ectoderm by adjacent dorsal mesoderm (Spemann's organizer) during
gastrulation. The CNS is characterized by a distinct anteroposterior (A-P)
patterning. The predominant model of how A-P patterning is established was
suggested by Nieuwkoop (Nieuwkoop,
1952) (reviewed in Doniach et al., 1993). In this two-step model,
the initial neural inducing signal specifies anterior neural tissues, such as
cement gland and forebrain; this first step is called `activation'. The second
caudalizing step is called `transformation'. During this step, anterior neural
tissue is respecified to more posterior fates, such as midbrain, hindbrain and
spinal cord. Several molecules have been identified which participate in the
`activation' and `transformation' processes. Non-neural ectoderm is induced to
anterior-neural tissue by inhibition of bone morphogenetic protein (BMP)
activity (reviewed in Harland and Gerhart,
1997
). Secreted BMP antagonists bind BMP and inhibit its
receptor-binding activity. BMP antagonists are expressed in Spemann's
organizer during gastrulation and induce anterior neural tissue in adjacent
ectoderm (Harland and Gerhart,
1997
). Three secreted factors were shown to caudalize neural
tissue in whole embryos or explants: retinoic acid, fibroblast growth factor
(FGF) and Xwnt3a (Durston et al.,
1989
; Sive et al.,
1990
; Ruiz i Altaba and
Jessell, 1991
; Sharpe,
1991
; Kolm and Sive,
1995
; Lamb and Harland,
1995
; Cox et al., 1995; McGrew
et al., 1995
; Blumberg et al.,
1997
). These pathways appear to interact to caudalize the
vertebrate CNS (reviewed in Gamse and
Sive, 2000
).
A characteristic of posterior neural tissue is its ability to undergo
convergent extension. This typical morphogenesis is restricted to the
hindbrain/spinal cord regions and does not occur in the more anterior
forebrain/midbrain regions (Keller et al.,
1992; Elul et al.,
1997
). Non-canonical Wnt planar cell polarity (PCP) pathway has
been shown to regulate convergent extension in dorsal mesoderm and
neuroectoderm of vertebrate and chordate embryos
(Wallingford et al., 2000
;
Heisenberg et al., 2000
;
Tada and Smith, 2000
;
Wallingford and Harland, 2001
;
Keys et al., 2002
). Most
recently, it has also been shown that FGF signaling might regulate mesodermal
and neural cell movements during mouse, chick and frog embryogenesis (Ciruna
et al., 2001; Mathis et al.,
2001
; Yokota et al.,
2003
). The full nature of the molecular interactions inducing both
neural marker expression and morphogenesis in the posterior CNS is still not
fully understood.
In this study, we examined how XMeis3 protein mechanistically controls cell
fate decisions in the hindbrain. XMeis3 is a transcription factor that could
act strictly in a cell-autonomous manner. However, because the XMeis3
gene is regionally expressed relatively early during development (early to
mid-gastrula stages), it is possible that XMeis3 could induce hindbrain by
activating non-cell-autonomous caudalizing pathways such as FGF, Wnt or
retinoic acid. Our previous studies showed that XMeis3 caudalizing activity is
dependent on mitogen-activated-protein kinase (MAPK) activity, presumably
through FGF signaling (Ribisi et al.,
2000). Two possible explanations could account for this
observation. XMeis3 protein could caudalize by direct activation of FGF/MAPK
signaling in neuroectoderm cells. Alternatively, basal FGF/MAPK signaling
might be required in ectoderm cells as a permissive competence factor that
enables caudalization by the XMeis3 protein.
We developed a technique to address the potential inductive non-cell-autonomous role for the XMeis3 protein in neural patterning. In this assay, animal cap ectoderm ectopically expressing XMeis3 protein was recombined with animal cap ectoderm neuralized by ectopic expression of the BMP dominant-negative receptor (DNR) protein. In these experiments, the XMeis3-expressing tissue induced mesoderm-independent convergent extension cell elongations in the adjacent juxtaposed neuralized explants. Elongated explants expressed the Krox20, HoxB3 (hindbrain) and n-tubulin (primary neuron) markers. Expression of the otx2 marker (forebrain) was extinguished in the elongated explants. Posterior neural gene expression was dependent on the presence of FGF/MAPK signaling but not canonical or PCP Wnt pathways, whereas convergent extension was dependent on both FGF and PCP activities. In ectoderm explants, ectopic XMeis3 induced FGF3 expression and subsequent activation of the MAPK pathway. Epistatic experiments suggest that XMeis3 activates FGF/MAPK, which in turn regulates PCP signaling. Thus, XMeis3 protein can act non-cell-autonomously to trigger a signaling cascade, which induces posterior neural marker expression and cell morphogenesis in the developing CNS. XMeis3-expressing cells establish a hindbrain induction center that regulates early A-P cell fate in the brain.
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Materials and methods |
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RT-PCR analysis
Reverse-transcription polymerase chain reaction (RT-PCR) was performed as
described previously (Wilson and Melton,
1994), except that random hexamers (100 ng per reaction) were used
for reverse transcription. Primers for EF1
, Krox20, HoxB9,
HoxD1 and XFGF3 were used
(Hemmati-Brivanlou and Melton,
1994
; Kolm et al.,
1997
; Domingos et al.,
2001
).
Western blot, immunostaining and luciferase analysis
MAPK (ERK) western blot analysis was performed using the Phospho-Plus
p44/p42 MAPK antibody kit (Cell Signaling / New England Biolabs) as described
(Henig et al., 1998).
Immunostaining of recombinant animal cap explants and marginal zone explants
with Tor70 was performed; tissue culture supernatant of Tor70 antibody was
used undiluted (Bolce et al., 1990). Bound antibodies were detected with
horseradish-peroxidase (HRP) conjugated secondary antibodies (goat anti-mouse
IgG; Pierce) diluted 1:100, and were visualized by HRP staining. After
fixation, explants were cleared in 1:2 benzyl alcohol/benzyl benzoate for
photography. GFP staining was performed by either fluorescent or
immunostaining analysis. Membrane-tagged GFP was detected with a primary
anti-GFP antibody (anti-GFP, rabbit IgG, Molecular Probes), followed by a
secondary rhodamine-red-conjugated anti-rabbit IgG (H+L) antibody (Jackson
Labs). dsh-GFP was analysed by three independent methods. (1) Direct GFP
fluorescence. (2) Previously described rhodamine detection. (3) HRP
immunohistochemistry. HRP-conjugated secondary goat anti-rabbit (IgG H+L,
BioRad) was used. Stained explants were cleared in 1:2 benzyl alcohol/benzyl
benzoate for viewing by bright-field or confocal microscopy (Zeiss Axioskop
and Radiance 2000, BioRad). Extract preparation and luciferase assays were
performed using the Luciferase Assay System (Promega) and activity was
measured by integrating total light emission over 30 seconds using a Berthold
luminometer. Luciferase activity was normalized to total protein
concentration.
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Results |
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Explant phenotypes showed that XMeis3 acts inductively. The XMeis3-injected
pigmented explant induced cell elongations in the adjacent neuralized albino
explant, unlike uninjected control recombinant explants
(Fig. 1B,E). Elongation
occurred at an average frequency of 70%, and did not occur (<5%) when
uninjected control animal caps were juxtaposed to neuralized animal caps
(Fig. 1C) or when
XMeis3-expressing animal caps were recombined with control animal caps
(Fig. 1D). We have examined
over 500 explants in each experimental group.
In addition to elongation analysis, in situ hybridization to hindbrain
(Krox20 r3/r5 and HoxB3 r5/r6)
(Bradley et al., 1992;
Godsave et al., 1998
) and
forebrain (otx2) (Blitz and Cho,
1995
) markers was also performed in these recombinant explants. In
the elongated albino explants, Krox20 and HoxB3 expression
was induced in comparison to control explants
(Fig. 2C-D,
Fig. 3A). Expression of
otx2 was high in the anteriorized albino cells in the control
recombinant explants (Fig. 2A),
but otx2 expression was extinguished in the elongated explants
(Fig. 2B). When otx2
expression was detected in recombinant explants, it was always expressed in
the distal tip of the explant, the furthest distance from the
XMeis3-expressing cells (Fig.
2B). In the few explants that failed to elongate
(Fig. 2B, asterisks),
otx2 expression was normal, thus resembling control recombinant
explants, which did not express XMeis3
(Fig. 2A). In some cases,
Krox20 expression appeared in two stripes, perhaps mimicking the
normal r3/r5 pattern (Fig. 2E).
HoxB3 expression always appeared in one stripe, deep within the
elongating explant, resembling the endogenous r5/r6 expression pattern
(Fig. 3A). Panneural marker
(nrp1) expression was unaltered in recombinant explants (not shown).
Expression of the neurogenic marker ntubulin
(Hollemann et al., 1998
) was
also activated in the elongated explants
(Fig. 3B); generally, XMeis3
activity and BMP antagonism alone are weak activators of n-tubulin
expression in isolated animal cap explants (not shown). These results suggest
that neuron cell fate specification was also induced in neuralized cells by
XMeis3-expressing cells, thus complementing the observation that
there is a large reduction of n-tubulin expression in XMeis3
knockdown embryos (Dibner et al.,
2001
).
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XMeis3 activates a caudalizing MAP kinase activity
XMeis3 caudalizes in a non-cell-autonomous manner, so we wanted to
determine whether XMeis3 acts through the FGF/MAPK pathway. Our previous
studies showed that XMeis3 protein could not caudalize in the presence of MAPK
pathway inhibitors such as dominant-negative Ras (N17Ras) or MAPK phosphatase
proteins (Ribisi et al.,
2000).
We determined whether XMeis3 protein could activate the FGF/MAPK pathway in
animal cap explants. One-cell embryos were injected with RNA encoding the
XMeis3 protein and blastula-stage animal cap explants were removed and
cultured until early to late gastrula stages. Protein extracts isolated from
the animal caps were assayed for phosphorylated ERK (activated MAPK) induction
by western analysis (Fig. 5A).
XMeis3 transiently induced significant levels of phosphorylated ERK in animal
cap explants (a tenfold increase) in comparison to controls
(Fig. 5A,B). These levels
declined by late neurula stages (not shown). To determine whether ERK
activation is dependent on FGF secretion through an active FGFI receptor,
one-cell embryos were co-injected with XMeis3- and
FGFI-DNR-encoding RNAs. In these explants, phosphorylated ERK levels
were very reduced (Fig. 5A,B)
and these explants also failed to express posterior neural markers
(Fig. 5C). These results show
that XMeis3 could caudalize the CNS by inducing MAPK activation through FGF
secretion. Complementing these results, ectopic XMeis3 levels activated
XFGF3 (Fig. 5D) and
XFGF8 (not shown) expression in neurula stage animal cap explants.
Interestingly, XFGF3 (Lombardo et
al., 1998) expression overlaps with XMeis3 in the early
neurula Xenopus hindbrain r4 region. To verify a role for FGF/MAPK
signaling in non-cell-autonomous XMeis3 caudal induction, RNA encoding the
N17Ras protein was co-injected with RNA encoding BMP DNR in the recombinant
explant assay. In comparison to controls, XMeis3-expressing animal
cap explants did not induce elongation
(Fig. 2F,G) and also did not
induce Krox20 expression (Fig.
2F) in adjacent explants expressing the N17Ras protein. Also,
otx2 expression was not extinguished in these explants
(Fig. 2G). Similar to N17Ras,
co-injection of FGFI DNR also inhibited elongation and Krox20
expression in neuralized recombinant explants (not shown). Thus, XMeis3
caudalizes juxtaposed anterior neuroectoderm via the FGF/MAPK signaling
pathway.
|
The Wnt-PCP pathway regulates convergent extension in both mesoderm and
neural cells (reviewed in Wallingford et
al., 2002). We were curious about whether PCP components regulate
convergent extension in recombinant explants. Elongation was strongly
inhibited in recombinant explants injected with RNAs encoding
dominant-negative Wnt 11 protein or PCP dominant-inhibitory disheveled (dsh)
proteins such as xdd1 and xdsh-D2 (Fig.
6A-D). Unlike the xdd1 mutant protein, which is
dominant-inhibitory to the canonical and PCP pathways, the xdsh-D2 mutant
protein still maintains the ability to activate canonical Wnt signaling.
Because the xdsh-D2 protein inhibited explant elongation, canonical Wnt
activity alone cannot be enough to induce convergent extension in the absence
of PCP activity. These results suggest that XMeis3-induced explant elongation
is dependent on an active PCP pathway, but independent of canonical Wnt
signaling.
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These results were supported by additional experiments in which BMP DNR
neuralized recombinant explants were co-injected with FGFI DNR protein and the
PCP constitutive activating form of Daam-1 protein (C-Daam-1). Daam-1 links
dsh to the membrane and its inhibition blocked convergent extension in embryos
and activin-treated animal cap explants
(Habas et al., 2001). C-Daam-1
rescued the antagonistic effects of dominant inhibitory PCP proteins on
activin-mediated elongations in animal cap explants
(Habas et al., 2001
). We found
that ectopic expression of C-Daam-1-encoding RNA partially rescued
cell elongations in neuralized explants that were inhibited by the FGFI DNR
protein (not shown).
These results place the PCP pathway downstream of FGF signaling. XMeis3 non-cell-autonomous caudalization activity is initiated through FGF signaling, which activates components of the PCP pathway. This induction drives neural convergent extension cell movements.
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Discussion |
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In elongated explants, expression of the Krox20 and HoxB3 hindbrain markers was induced. These hindbrain markers were expressed deeply within the elongated neural tissue. There was also a concomitant decline in forebrain-specific otx2 expression. In some elongating explants, Krox20 was expressed in two stripes, resembling the r3/r5 expression pattern in whole embryos. HoxB3 was always expressed as a single stripe within the elongating explants, resembling its normal expression pattern in r5/r6. In parallel, otx2 expression was extinguished in elongated explants or pushed into the most distal tip of the explant, the furthest from the XMeis3-expressing cells. This pattern of neural marker expression in the recombinant explants suggests that XMeis3 induces a rearrangement of neural pattern, which produces an A-P axis in the brain. In the recombinant explants, XMeis3-expressing cells send a signal to adjacent neuralized cells, which appear to recapitulate the normal process of A-P pattern formation (`activation and transformation') in the developing brain. These XMeis3-expressing cells form a hindbrain-inducing center, which can pattern the brain with a well-defined A-P symmetry.
Additionally, n-tubulin expression was also activated in the
elongated explants. N-tubulin is a marker of cells fated to
differentiate as neurons. Interestingly, XMeis3 and BMP antagonist activities
alone were weak activators of n-tubulin expression in animal cap
explants, yet in XMeis3 knock down embryos, there was large reduction of
ntubulin expression (Dibner et
al., 2001). These results suggest that XMeis3-inducing signals
interact with neuralized tissue to promote neurogenesis in the developing
embryo.
Previous studies in Xenopus showed that posterior neural
patterning was dependent on an active FGF/MAPK signaling
(Holowacz and Sokol, 1999;
Ribisi et al., 2000
).
Furthermore, we also showed that XMeis3 could not activate the expression of
posterior neural markers in isolated animal cap explants co-injected with MAPK
pathway inhibitors (Ribisi et al.,
2000
). XMeis3 appears to activate the FGF/MAPK pathway as part of
its caudalizing program. XMeis3 activated XFGF3 and XFGF8
(not shown) expression in isolated early-neurula-stage animal cap explants. In
these same explants, XMeis3 expression induced high
phosphorylated-ERK levels, in comparison to control explants. XMeis3
activation of ERK was dependent on the presence of an active FGFI receptor. In
recombinant explants, FGF signaling antagonist molecules expressed in the
neuralized explant side inhibited convergent extension and Krox20
expression mediated by juxtaposed XMeis3-expressing cells; in these
same recombinant explants otx2 expression was not inhibited. These
results demonstrate that XMeis3 non-cell-autonomously caudalizes anterior
neuroectoderm via the FGF/MAPK signaling pathway.
XFGF3 is expressed in overlapping r4 regions with XMeis3
in the early neurula Xenopus hindbrain
(Lombardo et al., 1998).
FGF3 and FGF8 are also expressed in the early chick and
zebrafish hindbrain (Mahmood et al.,
1995
; Maves et al.,
2002
), yet little is known about the expression pattern or role of
FGF8 protein in Xenopus hindbrain formation. FGF3/8
expression in r4 was sufficient to organize a hindbrain-inducing center in
zebrafish (Maves et al., 2002
;
Walshe et al., 2002
). Our
results suggest that XMeis3 organizes this hindbrain-inducing center by
activating FGF3 gene expression and subsequent protein secretion.
XMeis3 is initially expressed in a stripe of cells in the presumptive
hindbrain of late gastrula embryos, in the proper time and place to activate
this induction center. The observation that XMeis3 acts via FGF in a
non-cell-autonomous manner probably explains why hindbrain cells outside the
r2-r4 XMeis3 expression domain are lost in embryos expressing the
XMeis3 MO or antimorph protein (Dibner et
al., 2001
). The loss of XMeis3 activity in r2-4 eliminates this
induction center and so caudalization of the anterior CNS and pattern
formation of the whole hindbrain are disrupted.
Embryos knocked down by the XMeis3 antimorph protein or MO have a
significantly shortened body axis, strongly suggesting that neural convergent
extension in the hindbrain has been inhibited
(Dibner et al., 2001). XMeis3
knockdown embryos have very similar phenotypes to embryos in which the Wnt-PCP
pathway was inhibited in the neural plate
(Wallingford and Harland,
2001
). Supporting this conclusion, we have observed that neural
plate explants (cultured from late gastrula to late neurula stages) expressing
the XMeis3 MO elongate significantly less than normal explants (E.A.
and D.F., unpublished).
Canonical and non-canonical Wnt pathways have been shown to be involved in
posterior neural patterning and morphogenesis in vertebrate and chordate
embryos and explants. The canonical Wnt pathway was shown to caudalize the
Xenopus, chick and zebrafish CNS
(McGrew et al., 1995;
Kiecker and Niehrs 2001
;
Domingos et al., 2001
;
Nordstrom et al., 2002
;
Kudoh et al., 2002
). Canonical
Wnt and FGF signaling pathways apparently interact to pattern the vertebrate
CNS (McGrew et al., 1997
;
Domingos et al., 2001
;
Kudoh et al., 2002
;
Nordstrom et al., 2002
),
whereas Wnt-PCP activities regulate convergent extension cell movements in
both mesoderm and posterior neural cells
(Wallingford et al.,
2002
).
We determined whether PCP or canonical Wnt components were involved in the cell elongations detected in the recombinant explants. In recombinant explants injected with RNAs encoding PCP dominant-inhibitory proteins, convergent extension was inhibited. Elongations induced by XMeis3 in the adjacent neuralized explants were dependent on the PCP pathway but not the canonical-Wnt pathway, and ß-catenin activity could not trigger cell elongations in the absence of the PCP pathway. Antagonism of ß-catenin activity did not inhibit elongation in the neuralized explant or the activation of posterior neural markers by XMeis3 in isolated animal cap explants. This result suggests that XMeis3 induces posterior neural marker expression independently of canonical Wnt signaling. XMeis3 induces PCP activation in neuralized cells, because dsh-GFP protein was localized to the membranes of elongating recombinant explants only in the presence of adjacent XMeis3-expressing cells. In recombinant explants lacking XMeis3, dsh-GFP was found in a diffuse cytoplasmic manner. In isolated injected animal cap explants, inhibition of PCP activity had no drastic effect on posterior neural marker expression induced by XMeis3. Unlike FGF/MAPK pathway inhibition, in which XMeis3 induction of both posterior marker expression and elongation were strongly inhibited, PCP activity modulation prevented explant elongation but did not significantly alter posterior neural marker expression by XMeis3.
Convergent extension in the recombinant explants was dependent on both
FGF/MAPK and PCP pathways. The epistatic relationship of these two pathways
was determined. The BMP DNR/dsh-GFP neuralized recombinant explants were
co-injected with FGFI-DNR-encoding RNA. In the absence of FGF antagonism, dsh
was membrane localized in the elongated explants; in the presence of FGFI DNR,
explants did not elongate and dsh was not detected in the membrane. This
observation suggests that FGF/MAPK signaling lies upstream of the PCP pathway
and that dsh localization to the membrane is dependent upon functional FGF
signaling. Further supporting these results, we showed that FGFI DNR
inhibition of XMeis3-induced cell elongations could be partially rescued in
explants expressing the PCP constitutive activated form of the Daam-1 protein.
Daam-1 is a PCP component that links dsh to the membrane
(Habas et al., 2001).
A role for FGF signaling in early vertebrate mesodermal and neural
morphogenesis has been suggested (Ciruna et al., 2001;
Mathis et al., 2001), and most
recent experiments in dorsal mesoderm explants suggest that convergent
extension cell movements are regulated by FGF signaling
(Yokota et al., 2003
). Our
results place the PCP pathway downstream of FGF signaling in regulating neural
convergent extension. XMeis3 non-cell-autonomous caudalization activity is
initiated through FGF signaling, which activates the PCP pathway, leading to
membrane localization of the dsh protein in the neuralized explant. Thus, an
XMeis3 induction center in r2-r4 organizes hindbrain formation; this center
induces activation of FGF-dependent posterior neural marker expression and
morphogenetic cell movements characteristic of the hindbrain. Further studies
will determine which caudalizing components are required for the expression of
neural markers along the AP axis in comparison to the components regulating
neural cell movements. Investigation is needed to elucidate how XMeis3
coordinates FGF signaling, the three Wnt pathways (canonical, PCP and calcium)
and retinoid activities in order to make a hindbrain.
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ACKNOWLEDGMENTS |
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