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First published online 7 March 2007
doi: 10.1242/dev.003939
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Developmental Biology Unit, Université Pierre et Marie Curie (Paris VI) and CNRS, Observatoire Océanologique, 06230 Villefranche sur mer, France.
* Author for correspondence (e-mail: yasuo{at}obs-vlfr.fr)
Accepted 14 February 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: ephrin-Eph, ERK, Asymmetric cell division, Ciona, Notochord, Neural
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Knoblich, 2001;
Roegiers and Jan, 2004;
Betschinger and Knoblich,
2004). Although many such divisions have been described, the
underlying molecular mechanisms are currently understood in only a few cases
analysed in Drosophila melanogaster and Caenorhabditis
elegans. For the fly sensory organ precursors (SOPs) to generate two
distinct siblings, an asymmetrically distributed protein called Numb plays a
crucial role by attenuating Notch signals in one of the daughter cells and
thus creating differential transduction of the signalling pathway between the
daughter cells (Rhyu et al.,
1994; Guo et al.,
1996). A different mechanism controls the asymmetric cell division
of the Drosophila larval neuroblasts, in which the transcription
factor Prospero is asymmetrically inherited between the daughter cells and
acts as a binary switch between the self-renewal and differentiation fates
adopted by the daughters (Hirata et al.,
1995; Knoblich et al.,
1995; Choksi et al.,
2006). In both these cases, segregation of these factors in mother
cells appears to take place intrinsically
(Gho and Schweisguth, 1998;
Siegrist and Doe, 2006). In
another example, in C. elegans, during the cell division of an
embryonic cell named EMS, extrinsic cues, provided by a Wnt ligand, govern the
binary choice between endoderm and mesoderm fates of the resultant daughter
cells (Thorpe et al., 1997;
Rocheleau et al., 1997). This
extrinsic and directional Wnt signal, acting on the mother cell, results in a
differential nuclear accumulation of ß-catenin between the daughter
cells, and thus to their differential fate specification
(Goldstein et al., 2006;
Nakamura et al., 2005;
Lin et al., 1998). These
examples reveal that a variety of molecular strategies can be used to generate
two distinct cell fates following an asymmetric cell division.
One model system that could be particularly amenable to the study of
asymmetric cell division is the invertebrate chordate embryos of ascidians.
Ascidian embryogenesis is characterised by a fixed cell-cleavage pattern and a
small number of cells, which undergo fate restriction during the early
cleavage stages. These characteristics have led to a complete documentation of
cell lineages up to the onset of gastrulation
(Nishida, 1987). The cell
lineages have revealed that a number of cell divisions are coupled with the
differential segregation of cell fates between the sibling cells. We are
studying one such example, the generation of notochord and neural precursors,
from two pairs of mother cells named A6.2 and A6.4, located in an
anterior-marginal position of the 32-cell-stage embryo
(Fig. 1). Following cleavage of
these cells, the daughter cells that reside on the animal-pole side become
neural precursors and give rise to a part of the larval central nervous
system, whereas daughter cells arising on the vegetal-pole side become
precursors of the larval notochord (Fig.
1). It has been shown that the fibroblast growth factor (FGF)
pathway - involving the small GTPase Ras, MAPK/ERK kinase (MEK) and
extracellular-signal-regulated kinase (ERK) - plays a crucial role during this
differential fate specification (Nakatani
and Nishida, 1997; Kim and
Nishida, 2001). When FGF-ERK1/2 signals are inhibited, each mother
cell generates two neural precursors, instead of one notochord and one neural
precursor (Minokawa et al.,
2001; Yasuo and Hudson,
2007). Conversely, if isolated mother cells are treated with
exogenous FGF, both daughters adopt a notochord fate
(Minokawa et al., 2001;
Nakatani et al., 1996).
Consistent with these results, activation of ERK1/2 is detected in
notochord/neural mother cells but remains active only in the notochord
precursors following cell division (Yasuo
and Hudson, 2007). Thus, differential ERK activation between these
daughter cells, which is the first known sign of an asymmetry between them, is
the determinative event driving their binary cell fate choice. It has been
proposed that the differential activation of ERK1/2, and thus differential
fate specification of the two daughter cells, might be explained by a
directional FGF signal coming from the vegetal region (neighbouring endoderm
precursors) (Minokawa et al.,
2001). However, transcripts of FGF9/16/20, encoding the
FGF ligand responsible for ERK1/2 activation and early notochord induction,
are detected widely in vegetal cells, including in the notochord/neural mother
cells themselves, suggesting that it is unlikely to provide an asymmetric
positional cue (Imai et al.,
2002; Bertrand et al.,
2003).
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Hudson and Lemaire, 2001). All
data presented in this study were collected from at least two independent
experiments.
In situ hybridisation, immunohistochemistry and western blots
In situ hybridisation of Ciona embryos was carried out as
described previously (Hudson and Yasuo,
2006). Dig-probes were synthesised from the following cDNA clones:
Ci-Bra (Corbo et al.,
1997); Ci-ETR (Hudson
et al., 2003); Ci-ephrin-Ad (ciad008n17 from the Kyoto
Gene Collection Plates) (Satou et al.,
2002). For immunohistochemistry, embryos were fixed in 4%
paraformaldehyde/0.2% glutaraldehyde in artificial sea water for 30 minutes at
room temperature, washed with PBS, 0.1% Triton X-100 (PBST), blocked in PBST,
5% goat serum, 1% Roche Blocking Reagent, and incubated overnight in
anti-dpERK1/2 (Sigma, 1:1000) at 4°C. After washing in PBST, embryos were
incubated overnight in anti-mouse-HRP (Molecular Probes, 1:100) at 4°C and
then washed prior to signal detection, which was performed using TSA Plus
Fluorescence Systems (PerkinElmer) with cyanine 5 as fluochrome. Western blot
analyses were carried out following standard protocols with anti-dpERK1/2
(Cell Signaling Technology) and anti-rabbit-HRP (Jackson ImmunoResearch) used
at a dilution of 1:350 and 1:3000, respectively. A total of 20 embryos
dissolved in lysis buffer were used for each analysis.
Reagents
Ephrin-Ad-MO (5'-GGTAGTAGGTAAATTGAGTTGCCAT-3') was purchased
from GeneTools LLC and injected at a concentration of 0.5 mM. A
dominant-negative form of Eph3 was constructed using a cDNA clone, cieg009e01,
from the Kyoto Gene Collection Plates. cDNA fragments corresponding to the
entire extracellular domain, transmembrane domain and a part of intracellular
domain were PCR-amplified. For ephrin-Ad RNA, cDNA fragments corresponding to
the entire ORF was PCR-amplified from ciad008n17. Amplified cDNA fragments
were subcloned in pRN3 (Lemaire et al.,
1995) and used to synthesise RNAs. dnEph3 and ephrin-Ad RNAs were
injected at a concentration of 0.125 and 0.25 mg/ml, respectively.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and
Ci-ETR (Hudson et al.,
2003), respectively. The mean number of cells expressing
Ci-Bra in the A4.1-derived partial embryos was significantly higher
than that predicted from the cell lineage (6.4 versus 4;
Fig. 1 and
Fig. 2B,K). By contrast,
Ci-ETR-positive cells rarely formed (average of 0.8 cells), despite
the fact that the cell lineage predicts four neural precursors
(Fig. 1 and
Fig. 2G,K). Thus, when A4.1
progenitor cells are isolated, additional notochord precursors form at the
expense of neural precursors, indicating that interactions with other cells
are required for correct neural fate specification.
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Interaction with anterior-animal cells is required to repress notochord fate and induce neural fate in A4.1 lineages
We hypothesised that the inhibitory signals implicated in suppressing
notochord fate in the neural lineage may arise from the anterior-animal
lineage derived from a4.2 (blue in Fig.
1), because these cells are in contact with the A6.2 and A6.4
mother cells on the side on which the neural precursors will form. Using the
recently reported bioinformatics tool, 3D Virtual Embryo version 1.0
(Tassy et al., 2006), we
identified contacts between animal cells and notochord-neural mother cells at
the 24-cell stage. A6.2 contacts a5.3 with a contact area of 23.8% relative to
the entire cell surface of A6.2, whereas the A6.4 blastomere contacts a5.3
(10.9%), a5.4 (16.4%) and b5.3 (15.5%) with a total area of contact of 42.8%.
a5.3 and a5.4 cells originate from the a4.2 anterior-animal cell of the
eight-cell-stage embryo. We demonstrated that animal cells are indeed the
source of the notochord-inhibitory (neural inducing) signals by cell
co-isolation and recombination experiments. In A4.1 cells co-isolated with
a4.2 cells, the average number of Ci-Bra-positive cells at the
equivalent of the 110-cell stage was reduced to 3.2 cells
(Fig. 2C,K) compared with 6.4
cells in A4.1-derived partial embryos. Concomitantly, expression of
Ci-ETR was recovered with an average of 3.4 positive cells compared
with 0.8 cells in A4.1-derived partial embryos
(Fig. 2H,K). Similar results
were obtained when A4.1 and a4.2 cells were isolated separately and then
recombined (Fig. 2K) or when
A4.1 was recombined with b4.2 (mean of 3.1 cells positive for Ci-ETR
expression, n=16), but not when A4.1 was recombined with the vegetal
cells A4.1 or B4.1 (mean of 0.0 and 0.0 cells positive for Ci-ETR
expression; n=15 and n=10, respectively). These results
indicate that cell contact between mother cells and animal cells is required
to promote neural fate and suppress notochord fate in the neural
precursors.
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; Miao et al.,
2001). In particular, it has been shown that activation of EphA
leads to a rapid attenuation of ERK1/2 activity induced by other RTKs,
including those for platelet-derived growth factor (PDGF), epidermal growth
factor (EGF) and vascular endothelial growth factor (VEGF)
(Miao et al., 2001). Eph
receptors are activated by ephrin ligands. As ephrins are membrane-bound
proteins, ephrin-Eph signals are mediated in a cell-contact-dependent manner.
We first analysed the expression profiles, during early embryogenesis, of all
five ephrin genes annotated in the Ciona genome
(Satou et al., 2003). Among
the profiles obtained, the only appropriate spatial and temporal expression
was observed for Ci-ephrin-Ad, which encodes a GPI-anchored form of
ephrin ligand. Ci-ephrin-Ad starts to be expressed in all animal
cells at the 16-cell stage and its expression is maintained through the 24-
and 32-cell stages (Fig.
3A-D).
To address the potential role of Ci-ephrin-Ad in directing the
notochord-neural binary cell fate choice, we first overexpressed it by
injecting in vitro synthesised RNA into Ciona eggs. Injected eggs
were subsequently fertilised and cultured to the 64- and 110-cell stages for
the analysis of Ci-Bra and Ci-ETR expression, respectively.
Consistent with the idea that ephrin-Eph signals inhibit notochord fates,
expression of Ci-Bra was blocked following Ci-ephrin-Ad injection
(Fig. 4A-C). Furthermore,
notochord precursors now expressed the neural marker Ci-ETR,
suggesting that both of the daughter cells of A6.2 and A6.4 cells had adopted
a neural fate (Fig. 4E,F,G).
This effect of Ci-ephrin-Ad overexpression phenocopied that of the inhibition
of FGF-MEK signals (Minokawa et al.,
2001; Yasuo and Hudson,
2007), suggesting that activation of ephrin-Eph signals can
inhibit the FGF-Ras-MEK-ERK pathway in ascidian embryonic cells. This was
directly addressed by using an antibody recognising the activated,
diphosphorylated form of ERK1/2, for which there is a single representative in
the Ciona genome (Satou et al.,
2003). Strikingly, activation of ERK1/2 in Ci-ephrin-Ad-injected
embryos was blocked as efficiently as in sibling embryos treated with UO126, a
pharmacological inhibitor for MEK (Favata
et al., 1998) (Fig.
5A). Furthermore, immunohistochemistry on whole embryos showed
that ERK1/2 activation was inhibited throughout the embryo following
Ci-ephrin-Ad injection (Fig.
5C).
Ephrin-Eph signals are known to act bi-directionally; receptor signalling
is referred to as forward signalling and ephrin-ligand signalling as reverse
signalling (Cowan and Henkemeyer,
2002; Murai and Pasquale,
2003). We thus asked whether the effect of Ci-ephrin-Ad on ERK1/2
activity was mediated via forward or reverse signalling. Transcripts of two of
the five Ciona Eph receptor genes, namely Ci-Eph2 and
Ci-Eph3, showed a broad distribution during the early cleavage
stages. We generated a dominant-negative form of Ci-Eph3 (dnEph3) by removing
most of its intracellular domain. Co-injection of RNAs for dnEph3 and
Ci-ephrin-Ad completely suppressed the ephrin-mediated inhibition of ERK1/2
activation (Fig. 5A),
demonstrating that Ci-ephrin-Ad attenuates ERK1/2 activation via Eph
receptors.
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Ephrin-Ad is required for the asymmetric cell division of isolated mother cells
The studies described above identified ephrin-Ad as a major factor
controlling the binary fate choice of the notochord and neural precursors in
the context of whole embryos, but did not reveal whether it does so by acting
on the mother cell or on the neural-fated daughter cell. To address this
issue, we isolated notochord/neural mother cells from uninjected or
ephrin-Ad-MO-injected embryos at the late 32-cell stage, and monitored
Ci-Bra and Ci-ETR expression at the equivalent of the early
gastrula stage (Fig. 6A).
Similar to the result shown in Fig.
2L, mother cells isolated from control late 32-cell-stage embryos
developed into four-cell partial embryos expressing Ci-Bra and
Ci-ETR in average of 1.6 and 1.9 cells, respectively
(Fig. 6B). By contrast, the
resultant partial embryos developed from mother cells isolated from
ephrin-Ad-MO-injected embryos produced more notochord cells (2.9 cells) at the
expense of neural cells (0.5 cells) (Fig.
6B). These results show that ephrin-Ad is indeed acting on the
notochord/neural mother cells and is required for their autonomous capacity to
generate two distinct daughter cells, with ephrin-Ad promoting the neural
daughter cell fate.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Roegiers and Jan,
2004; Betschinger and Knoblich,
2004) (see also Horvitz and
Herskowitz, 1992; Morrison and
Kimble, 2006). The second type does not involve polarisation of
the mother cell but involves the asymmetric placement of equivalent daughter
cells relative to extrinsic instructive cues, thus resulting in their adoption
of distinct fates (Horvitz and Herskowitz,
1992; Morrison and Kimble,
2006). We have shown that the cell division of the
notochord/neural mother cell in Ciona embryos can be considered as
truly `asymmetric' because, in isolation, this cell is able to divide
autonomously to generate two daughter cells with distinct fates. This
asymmetric cell division is dependent on cellular interactions between the
mother cell and adjacent animal cells, and requires ephrin-Eph signalling. We
have found that Ci-ephrin-Ad, present in animal cells, signals via Eph
receptors to the mother cells, which is required for them to divide into two
distinct daughter cells, with ephrin-Ad promoting the neural daughter cell
fate. Our study also demonstrates that the ephrin-Eph signal acts via
attenuation of ERK activation in the neural precursor. Based on these
findings, we propose the following model for the asymmetric cell division of
notochord/neural mother cells. While broadly expressed FGF9/16/20 activates
the Ras-MEK-ERK pathway in the mother cell, directional ephrin-Ad signals from
the animal cells act in parallel to functionally polarise the mother cell.
Local activation of the ephrin-Eph signal in the mother cell becomes manifest,
following cell division, as the selective attenuation of ERK activation in the
neural-fated daughter cell, thus resulting in the differential fate
specification of the daughter cells as notochord (ERK on) and neural (ERK off)
precursors.
It will be of great interest in future studies to unravel the precise
molecular cascade acting downstream of ephrin-Ad-Eph signalling in order to
understand how this activity becomes spatially restricted within the mother
cell prior to its division, and how this leads to the differential attenuation
of ERK activation between the daughter cells following division. RTKs,
including Eph, commonly signal through cytoplasmic proteins with SH2 domains,
which bind either directly to phosphotyrosine sites on the activated receptor
or to phosphorylated docking proteins. A variety of SH2 proteins have been
identified as potential Eph receptor-binding partners
(Hock et al., 1998;
Holland et al., 1997). Among
them is the p120-Ras GTPase-activating protein (p120-RasGAP), which is a
negative regulator of the Ras small G protein
(Hock et al., 1998;
Holland et al., 1997) and has
been shown to be required for EphB2- and EphA2-mediated attenuation of ERK1/2
in NG108 neuronal cell lines and mouse embryonic fibroblasts, respectively
(Elowe et al., 2001;
Tong et al., 2003). It is
tempting to speculate that activation of ephrin-Ad-Eph signals results in the
recruitment of p120-RasGAP to a sub-membrane domain on the animal-pole side of
the A6.2 and A6.4 mother cells, and that the subsequent cytokinesis of the
mother cells results in the partitioning of the RasGAP-enriched sub-membrane
domain only to the future neural daughter cells.
|
). Our
current study adds to the list a new role for ephrin-Eph signals - a role in
cell fate specification coupled with an asymmetric cell division. The current
study also provides compelling evidence that activation of the ephrin-Eph
signalling pathway can result in attenuation of ERK1/2 activation in the
context of embryonic development, in addition to the examples in cell lines
and during C. elegans oocyte maturation
(Elowe et al., 2001;
Miao et al., 2001;
Miller et al., 2003).
RTK-mediated ERK1/2 activation is responsible for the control of a wide
variety of developmental processes requiring spatial and temporal precision
(Christen and Slack, 1999;
Corson et al., 2003;
Eblaghie et al., 2003;
Gabay et al., 1997;
Sawada et al., 2001;
Shinya et al., 2001). Thus, it
will be important to determine whether ephrin-Eph signalling acts more
generally, in additional developmental contexts, as a potent local regulator
of the RTK-ERK signalling pathway. In conclusion, we have revealed a novel mechanism of asymmetric cell division based on ephrin-Eph signalling and selective ERK attenuation, broadening our knowledge of the diverse mechanisms used to control these specialised cell divisions. It will now be important to address whether ephrin-Eph signalling is playing similar roles in additional developmental and cellular contexts.
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ACKNOWLEDGMENTS |
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0.01). n, total number of samples
analysed.