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First published online May 9, 2008
doi: 10.1242/10.1242/dev.019893
1 Department of Biology, Graduate School of Sciences, Kyushu University,
Hakozaki 6-10-1, Fukuoka 812-8581, Japan.
2 Faculty of Integrated Arts and Sciences, The University of Tokushima,
Minamijyousanjima-cho 1-1, Tokushima 770-8502, Japan.
3 CREST, Japan Science and Technology Agency, Nihonbashi, Tokyo 103-0027,
Japan.
* Authors for correspondence (e-mails: nnakascb{at}mbox.nc.kyushu-u.ac.jp; nsagascb{at}mbox.nc.kyushu-u.ac.jp)
Accepted 7 April 2008
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Xenopus, Neural differentiation, Cell division, FoxM1, Cdc25B, BMP
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Stern,
2005). During gastrulation in Xenopus, BMP inhibition
induces the expression of Sox2, an initial-stage neural marker that specifies
the formation of neuroectoderm (Kishi et
al., 2000). Subsequently, Xngnr1 (a Xenopus
neurogenin-related bHLH factor) is expressed in a subset of the
neuroectodermal cells to generate primary neurons, which form the simple
nervous system of early embryos (Ma et
al., 1996). Xngnr1 activates certain neurogenic regulators, such
as NeuroD, in primary neuronal precursors and thereby promotes neuronal
differentiation (Lee et al.,
1995; Ma et al.,
1996). Other factors, such as Notch and Delta, are also expressed
in the neuroectoderm and play positive or negative roles in neuronal
differentiation (Bertrand,
2002).
Neuroectodermal cells have a higher mitotic activity than
non-neuroectodermal cells in Xenopus embryos
(Saka and Smith, 2001), and
neural precursors actively proliferate in both chick and mouse embryos
(Graham et al., 2003;
Hollyday, 2001). Neural
precursors exit from the cell cycle and differentiate into functional neural
cells, owing in part to the actions of Cdk inhibitors, such as
p27Xic1 in Xenopus
(Vernon et al., 2003) and
p27Kip1/p57Kip2 (Cdkn1b/Cdkn1c - Mouse Genome
Informatics) in mouse (Cremisi et al.,
2003). However, it remains unclear how cell proliferation is
initially stimulated in the neuroectoderm or neural precursors. Furthermore,
it is unknown whether preceding cell division or proliferation is required for
terminal differentiation of neural precursors, although, in Xenopus,
cell division after the onset of gastrulation has long been thought to be
nonessential for neural differentiation
(Harris and Hartenstein, 1991;
Rollins and Andrews, 1991;
Yeo and Gautier, 2003).
The Fox gene family encodes transcription factors containing a conserved
Forkhead DNA-binding motif (Katoh and
Katoh, 2004). FoxM1 has been isolated from both mammals and
Xenopus (Pohl et al.,
2005; Ye et al.,
1997). In mammalian cultured cells, FoxM1 activates the expression
of many genes, particularly those encoding G2-M cell-cycle regulators, such as
cyclin B and Cdc25B, and thereby promotes cell division
(Laoukili et al., 2005;
Wang et al., 2005). Although
Foxm1 is expressed in actively proliferating neural precursors in mouse
(Karsten et al., 2003), little
is known about whether this expression makes any contribution to the
proliferation or differentiation of neural precursors
(Krupczak-Hollis et al., 2004;
Schüller et al.,
2007).
To investigate the possible relationship between cell division and neural differentiation, we have analyzed the role of FoxM1 in early Xenopus development. We show that FoxM1 is expressed in the neuroectoderm and is required for cell division in this region. In addition, BMP inhibition induces cell division by augmenting the expression of FoxM1 and its target G2-M regulators. Furthermore, and importantly, preceding FoxM1-dependent cell division is required for neuronal differentiation but not specification. Thus, our results reveal the primary mechanism of proliferation of neural precursors, and link cell division and neuronal differentiation in early Xenopus embryos.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
Antisense MOs were obtained from Gene Tools (Philomath, OR). MO sequences were
as follows (5' to 3'): FoxM1-MO, GCTTGTTCTCATGGTGTGACGGCTC;
Cdc25B-MO, TGTGTGAGGCTCTGGCCTGGGAAC; and control MO,
CCTCTTACCTCAGTTACAATTTATA.
cDNAs and in vitro transcription
cDNAs encoding Xenopus FoxM1
(Pohl et al., 2005) (accession
number AJ853462) and cyclin B3 (Hochegger
et al., 2001) (AJ853462) were isolated by RT-PCR from
Xenopus neurula RNA and subcloned into either the pT7-G (UKII+) or
pCS2+ transcriptional vector (Nakajo et
al., 2000; Watanabe and
Whitman, 1999). The FoxM1(
N) cDNA encoding amino acids
215-759 of Xenopus FoxM1 protein was as previously described
(Lüscher-Firzlaff et al.,
2006). A cDNA encoding Xenopus Cdc25B (AB363840) was
isolated by PCR from a tailbud cDNA library and subcloned into the pT7-G
(UKII+) or pCS2+ transcriptional vector. cDNAs encoding dnBMPR and Noggin were
as previously described (Graff et al.,
1994; Smith and Harland,
1992). In vitro transcription of cDNAs was performed as described
(Nakajo et al., 2000).
RT-PCR
RT-PCR of RNA from whole embryos or animal caps was performed essentially
as described (Watanabe and Whitman,
1999). The primer sets used for PCR were (5' to 3'; U,
upstream and D, downstream): FoxM1 U, CCGACCACCTCTTCCACTCCCAGC and D,
GTCCAGCAGAATTTTGCTTAGACTGTCGT; Cdc25B U, ACGTGGAAGACTTTCTGCTGAAG and D,
TCTCGCTTGCTCTTGTCTCCGG; cyclin B1 U, GATGGTGGATTATGATATGG and D,
CCATTTCCACAACAACATCT; cyclin B3 U, CTTCCTGCGCAGATTTGCTA and D,
TGTGAGTATTTGCTCCTCAC; cyclin D1 U, ACTGACTGAGGATACCAAGC and D,
GGAGATGTCCACTTCATCCA; Sox2 U, GCTGCCCATGCACCGCTATGATG and D,
TCACATGTGCGACAGAGGCAGCG.
Primer sets for N-CAM, N-tubulin, E-keratin, M-actin and EF1-
are
described in Xenbase
(http://www.xenbase.org/common).
Whole-mount in situ hybridization, β-Gal staining and pH3 staining
Whole-mount in situ hybridization was performed essentially as described
(Sive et al., 2000); the
constructs used were for Sox2 (Mizuseki et
al., 1998), Xngnr1 (Ma et al.,
1996), N-tubulin (Chitnis et
al., 1995) and MyoD (Hopwood
et al., 1989). Staining for β-galactosidase (β-Gal) and
phosphorylated histone H3 (pH3) were as described (Saka and Smith, 2002;
Sive et al., 2000).
Hoechst staining
Neural plates were isolated from embryos at stage (st.) 14, fixed with
MEMFA for 20 minutes, stained for β-Gal and then re-fixed with Fixative 1
[10% formaldehyde, 60 mM HEPES-KOH (pH 7.5)] for 1 hour. They were then
treated with Fixative 2 [10% formaldehyde, 60 mM HEPES-KOH (pH 7.5), 50%
glycerol] containing 5 µg/ml Hoechst for 15 minutes, washed twice with
Fixative 2 (without Hoechst) and then mounted for fluorescence microscopy.
Antibodies and immunoblotting
For immunoblotting, whole embryos or animal caps were homogenized with an
extraction buffer (80 mM β-glycerophosphate, 15 mM MgCl2, 20
mM EGTA, 10 µM pepstatin A, 10 µg/ml leupeptin, 10 µg/ml aprotinin,
0.2 mM PMSF, 1 mM NaF, 1 µM microcystin, 1 mM sodium orthovanadate).
Proteins equivalent to one embryo or ten animal caps were analyzed by
immunoblotting using antibodies against histone H3 phospho-Ser10 (Upstate
Biochemistry) or ERK1 (Santa Cruz Biotechnology).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Using
whole-mount in situ hybridization (WISH), FoxM1 mRNA was detected
principally in the animal hemisphere at the initial gastrula stage (st. 10),
in the neural plate at the early neurula stage (st. 14), in the neural tube at
the late neurula stage (st. 19), and in the head region and eye primordium at
the tailbud stage (st. 25) (Fig.
1A, lower panels). Given these results and the major role of FoxM1
in G2-M cell-cycle progression (Laoukili
et al., 2005; Wang et al.,
2005), in post-gastrula embryos FoxM1 might be involved in cell
proliferation, particularly in the neural region. To test this possibility, we
knocked down FoxM1 using antisense morpholino oligos (MO), which,
upon injection, were able to effectively suppress translation of ectopic
FoxM1 mRNA in early embryos (see Fig. S1 in the supplementary
material). Injecting FoxM1-MO into one-cell embryos had no appreciable effects
on the external morphology of embryos, at least until the mid-neurula stage
(data not shown, but see Fig.
3B). Then we analyzed mitotic cells in the neural plate of early
neurula embryos (st. 13) by immunostaining for mitotic Ser10-phosphorylated
histone H3 (pH3) (Saka and Smith,
2001). Injection of FoxM1-MO into one blastomere of a two-cell
embryo caused a 
70% reduction in the number of pH3-positive cells in the
neural plate on the injected side, whereas injection of control MO caused no
appreciable reduction (Fig.
1B). We also counted the number of cells in the neural plate
(isolated from st. 14 embryos) by staining their nuclei with Hoechst.
Injection of FoxM1-MO, but not of control MO, caused a significant (25%)
reduction in cell numbers in the neural plate, as well as causing an
enlargement and a stronger staining of nuclei (probably reflecting G2-phase
arrest of the cell cycle) (Fig.
1C). Thus, intriguingly, FoxM1 is essential for normal cell
proliferation in the neural plate, consistent with it being expressed in this
region (Fig. 1A).
FoxM1 activates expression of G2-M cell-cycle regulators in the neural plate
Because FoxM1 activates many genes encoding G2-M cell-cycle regulators,
such as Cdc25B and cyclin B, in cultured cells
(Laoukili et al., 2005;
Wang et al., 2005), it might
also do so in the neural plate, thereby promoting cell proliferation in this
region. When analyzed by WISH at the mid-neurula stage (st. 15-16), both
Cdc25B and cyclin B3, like FoxM1, were found to be expressed
in the neural plate (Fig. 1D,
control MO). More importantly, pre-injecting FoxM1-MO into two-cell embryos
significantly suppressed the expression of Cdc25B (in 81% of the
injected embryos, n=52) and cyclin B3 (88%, n=51) in the
neural plate (Fig. 1D,
FoxM1-MO; see the right-hand, injected side of the embryos). To confirm these
results, we also performed RT-PCR analysis of Cdc25B and cyclin B3
using whole embryos. FoxM1-MO injection at the one-cell stage caused a
dramatic reduction in the expression of Cdc25B and cyclin B3 at the
initial neurula stage (st. 13) (Fig.
1E). Furthermore, immunoblotting analysis, like immunostaining
analysis (Fig. 1B), revealed a
substantial decrease in pH3 levels in FoxM1-MO-treated embryos
(Fig. 1E). Importantly, all of
these effects of FoxM1-MO injection were rescued by co-injection of
FoxM1-MO-resistant mRNA encoding wild-type FoxM1 (but not a transcriptionally
inactive FoxM1 mutant, data not shown)
(Fig. 1E). Thus, these results
suggest that FoxM1 promotes cell proliferation in the neural plate, most
probably by transcriptionally activating the expression of G2-M cell-cycle
regulators (see also Fig.
4C).
BMP inhibition induces cell proliferation in the neuroectoderm
Although cell proliferation is pronounced in the proneural region in many
species (Hollyday, 2001;
Saka and Smith, 2001)
(Fig. 1B), little is known
about the identity of the signaling that leads to this proliferation. In
vertebrates, including Xenopus, neural induction involves signaling
induced by FGF, Wnt, or by inhibition of BMP
(Muñoz-Sanjuán and
Brivanlou, 2002; Stern,
2005). To test whether any of these signaling pathways could
induce cell proliferation in the neural plate
(Fig. 1B), we performed animal
cap assays, in which the effect of a single signaling pathway on neural
induction or differentiation can be tested
(Stern, 2005). As revealed by
immunoblotting of pH3, BMP inhibition by ectopically expressed Noggin [a BMP
antagonist (Muñoz-Sanjuán
and Brivanlou, 2002)], but not FGF or Wnt signaling, strongly
induced cell proliferation in the animal cap, although the three signaling
pathways (induced by Noggin, FGF or Wnt) were all effectively activated, as
judged by expression of their downstream genes (N-CAM, Xbra and
M-actin, respectively) (Fig.
2A). Similar to BMP inhibition by Noggin, BMP inhibition by
Chordin (another BMP antagonist) or a dominant-negative BMP receptor (dnBMPR),
also induced cell proliferation in the animal cap (see Fig. S2A in the
supplementary material). Moreover, even overexpression of dnBMPR in early
neurula embryos was able to significantly enhance cell proliferation in the
ventral region (Fig. 2B). In
Xenopus, inhibition of BMP signaling is initiated during gastrulation
and is central to neural induction
(Muñoz-Sanjuán and
Brivanlou, 2002; Stern,
2005) (see also below). Thus, these results strongly suggest that
BMP inhibition induces not only neural induction, but also cell proliferation,
in the neural plate (or neuroectoderm) of Xenopus embryos.
|
N)
(Lüscher-Firzlaff et al.,
2006)] alone was able to induce both the expression of the G2-M
regulators (but not of cyclin D1) and cell proliferation in the animal cap,
albeit significantly less strongly than Noggin could
(Fig. 2D). Taken together,
these results strongly suggest that BMP inhibition activates the expression of
FoxM1 and hence that of G2-M cell-cycle regulators, thereby promoting
cell proliferation in the neuroectoderm.
|
), was
markedly reduced in FoxM1-MO-treated (but not control) embryos, whereas
expression of M-actin (a muscle marker) and E-keratin (an epidermal marker)
were unaffected (Fig. 3A,
right). Importantly, all the effects observed with FoxM1-MO injection were
rescued by co-injection of FoxM1-MO-resistant FoxM1 mRNA
(Fig. 3A). Thus, these results
show that FoxM1 is required specifically for neural development, but not for
epidermal or muscular development.
FoxM1 is required for neuronal differentiation but not specification
To investigate the role of FoxM1 in neurogenesis in more detail, we next
examined expression of several neural markers in mid-neurula embryos (st. 14
or 16) by WISH. Treating embryos with FoxM1-MO, but not control MO, markedly
inhibited the expression of N-CAM as a pan-neural marker (91%,
n=51) and of N-tubulin (which was expressed in stripes) (90%,
n=60) (Fig. 3B).
However, expression of Xngnr1, a proneural marker specifying primary
neurons (Ma et al., 1996), was
not affected by FoxM1-MO treatment (7%, n=43), whereas that of
Sox2, an initial neural marker specifying neuroectoderm
(Kishi et al., 2000), was
slightly expanded (79%, n=63)
(Fig. 3B). As a control,
expression of MyoD, a mesodermal marker, was not affected by FoxM1-MO
(4%, n=46). In these experiments, the decrease in N-tubulin (and
N-CAM) expression induced by FoxM1-MO could have been due to the
decrease in cell number. However, double staining of nuclei and N-tubulin mRNA
revealed that, in the FoxM1-MO-treated (primary) neuronal region, the cell
number was only moderately reduced (by about 25%), whereas the expression of
N-tubulin was totally suppressed (see Fig.
1C and Fig. S3 in the supplementary material), indicating that the
decrease in N-tubulin expression induced by the FoxM1-MO was not a matter of
cell number. Thus, the present data seemed to suggest that FoxM1 is required
for (primary) neuronal differentiation, but not for neuronal specification, in
early embryos.
To confirm the requirement of FoxM1 for neuronal differentiation (but not
specification), we also performed RT-PCR analysis of various marker genes
using animal caps treated with Activin or Noggin. Activin treatment of animal
caps induced the expression of M-actin, N-CAM and N-tubulin, as
previously reported (Hemmati-Brivanlou and
Melton, 1992) (Fig.
3C, control MO); notably, however, co-treatment with FoxM1-MO
suppressed the expression of N-CAM and N-tubulin but not of M-actin
(Fig. 3C, FoxM1-MO). By
contrast, Noggin treatment induced the expression of Sox2 and
N-CAM, as previously reported
(Stern, 2005), and also of
N-tubulin (Fig. 3D, control
MO); however, co-treatment with FoxM1-MO suppressed the expression of
N-CAM and N-tubulin but not of Sox2
(Fig. 3D, FoxM1-MO). Ectopic
expression of FoxM1(N) alone was not able to induce
expression of the neural markers, including Sox2 (data not shown, but
see Fig. 2D). Finally, and as
expected, the onset of FoxM1 expression in Noggin-treated animal caps
coincided with that of Sox2 but preceded that of N-CAM and
N-tubulin (which occurred in this order)
(Fig. 3E; see also
Fig. 3E legend). Together with
the results shown in Fig. 3B,
these results strongly suggest that FoxM1 is required (albeit not sufficient)
for neuronal differentiation, but not specification, in early
neurogenesis.
|
).
However, MO against Cdc25B mRNA, which strongly inhibited the
expression of Cdc25B protein at the gastrula stage (see Fig. S4B in the
supplementary material), caused obvious defects in head formation and eye
development at the late tailbud stage (st. 32)
(Fig. 4B). Specifically, at the
initial neurula stage (st. 13), Cdc25B-MO caused a significant reduction in
cell division in the neural plate (and in Noggin-treated animal caps, data not
shown) (Fig. 4C), consistent
with Cdc25B being expressed in this region
(Fig. 1D). More importantly,
Cdc25B-MO markedly inhibited the expression of N-tubulin (88%, n=60)
in early neurula embryos (st. 14) (Fig.
4D); it also inhibited the expression of N-CAM and
N-tubulin, but not of Sox2 or M-actin, in the animal caps treated
with Noggin or Activin (Fig.
4E). Clearly, all of these results
(Fig. 4B-E) are very similar to
those obtained with FoxM1 knockdown
(Fig. 1B,
Fig. 3A-D), suggesting that
Cdc25B acts downstream of FoxM1 not only for proliferation, but also for
differentiation, of neuroectodermal cells. Indeed, ectopic expression of
Cdc25B efficiently rescued the effects of FoxM1-MO on both the
external morphology and the expression of N-CAM and N-tubulin
(Fig. 4F). Thus, these results
indicate that FoxM1 is involved in neuronal differentiation via its function
in promoting G2-M cell-cycle progression in neuroectodermal cells. This would
in turn suggest that preceding, FoxM1-dependent cell division is required for
differentiation of neuronal precursors in early Xenopus embryos (see
Fig. 5 and Discussion).
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), induced cell
proliferation in the neuroectoderm by augmenting the expression of
FoxM1 and its target G2-M regulators
(Fig. 2). BMP is a member of
the transforming growth factor-β (TGF-β) superfamily
(Feng and Derynck, 2005), and
TGF-β can inhibit proliferation of epithelial cells in mammals
(Massagué et al.,
2000). Interestingly, BMP (inhibition), like TGF-β
(Ko et al., 1995), influenced
the expression of the G1-S regulator cyclin D1
(Fig. 2C and see Fig. S2A in
the supplementary material). More interestingly, forced activation of BMP
signaling (in Noggin-treated animal caps) suppressed the expression of
FoxM1 and G2-M cell-cycle regulators (see Fig. S2B in the
supplementary material). Thus, it seems that active proliferation of
(prospective) neuroectodermal cells after BMP inhibition is due, at least in
part, to inhibition of the ability of BMP to inhibit FoxM1 expression
and hence cell proliferation. Given the various roles of BMPs in embryogenesis
(Hogan, 1996), our findings
may imply that BMP signaling regulates cell proliferation, in addition to cell
fate, in many situations. In any event, our results reveal that BMP inhibition
induces not only neural induction, but also FoxM1-dependent cell
proliferation, in the neuroectoderm.
We also found that FoxM1 is required for neural but not epidermal or
muscular development (Fig. 3A).
More specifically, FoxM1 was required for primary neuronal differentiation but
not specification (Fig. 3B-E).
Furthermore, and interestingly, FoxM1 was involved in neuronal differentiation
via its function in promoting G2-M cell-cycle progression, or primarily via
activating Cdc25B expression (Fig.
4). According to the temporal expression patterns of neural
induction and differentiation markers in Xenopus
(Chitnis et al., 1995;
Ma et al., 1996;
Mizuseki et al., 1998) (see
also Fig. S5 in the supplementary material), neural induction (or
specification) occurs during gastrulation (st. 10-12), whereas primary
neuronal differentiation occurs during the subsequent neurula stages (st.
13-16) (see Fig. 5). Moreover,
according to previous reports (Hartenstein,
1989; Howe et al.,
1995; Lamborghini,
1980), primary neuronal precursors presumably undergo only one or
two rounds of cell division between the onset of gastrulation (st. 10) and
neuronal differentiation (which is accompanied by cell-cycle exit) (st.
13-16). Therefore, our findings that Cdc25B, the FoxM1 target, begins
to be expressed at st. 10 (see Fig. S4A in the supplementary material) and
that FoxM1/Cdc25B-dependent cell division before or at st. 13
(Fig. 1B-E,
Fig. 4C) is required for
neuronal differentiation at st. 14 (Fig.
3B, Fig. 4D), would
seem to suggest that FoxM1 functions to drive the immediate, preceding cell
division(s) of primary neuronal precursors for their terminal differentiation
(Fig. 5). Furthermore, the
continued expression of FoxM1 (and its target G2-M cell-cycle
regulators) in later neural tissues (Fig.
1A), as well as its requirement for head formation and eye
development (Fig. 3A,
Fig. 4B), suggests that
FoxM1-driven cell division is also required to generate secondary neurons
(Harris and Hartenstein, 1991;
Hartenstein, 1989). Thus, it
seems that FoxM1 functions to link cell division and neuronal differentiation
in early Xenopus embryos.
|
;
Rollins and Andrews, 1991;
Yeo and Gautier, 2003). In
these studies, however, cell division was inhibited using hydroxyurea and/or
aphidicolin, either of which causes S-phase arrest
(Dasso and Newport, 1990).
Hence, it seems likely that a prolonged S phase caused by
hydroxyurea/aphidicolin might allow, in some way, the expression of some
crucial neurogenic regulator(s) that would normally be expressed just prior
to, and function for, neuronal differentiation. Such a neurogenic
regulator(s), however, would not be expressed or function in FoxM1-depleted
embryos, in which neuroectodermal cells, although specified to neuronal
precursors, cannot differentiate into neurons, most likely owing to G2-phase
arrest. In any event, in normally developing embryos, cell division occurs and
neuronal precursors advance to the postmitotic phase, only within which can
the precursors differentiate into neurons
(Hartenstein, 1989;
Lamborghini, 1980). Our
results suggest that FoxM1 is essential for such cell division and, hence, for
neuronal differentiation (Fig.
5). Thus, it appears that under normal conditions, preceding cell
division is required for neuronal differentiation.
The requirement of BMP inhibition for neural induction is highly conserved
from Drosophila to mammals
(Muñoz-Sanjuán and
Brivanlou, 2002; Stern,
2005). Furthermore, in many species, neural precursors actively
proliferate prior to their terminal differentiation
(Graham et al., 2003;
Hollyday, 2001). Thus, given
our results, FoxM1 or some other functionally equivalent transcription
factor(s) might also play an important role in the proliferation and
differentiation of neural precursors in other species.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/11/2023/DC1
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ACKNOWLEDGMENTS |
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