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First published online April 24, 2009
doi: 10.1242/10.1242/dev.021246
Review |
1 Institute for Stem Cell Research and MRC Centre for Regenerative Medicine,
University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ,
UK.
2 Division of Cell and Developmental Biology, College of Life Sciences,
University of Dundee, Dow Street, Dundee DD1 5EH, UK.
* Author for correspondence (e-mail: k.g.storey{at}dundee.ac.uk)
SUMMARY
The progressive generation of chick and mouse axial tissues – the spinal cord, skeleton and musculature of the body – has long been proposed to depend on the activity of multipotent stem cells. Here, we evaluate evidence for the existence and multipotency of axial stem cells. We show that although the data strongly support their existence, there is little definitive information about their multipotency or extent of contribution to the axis. We also review the location and molecular characteristics of these putative stem cells, along with their evolutionary conservation in vertebrates and the signalling mechanisms that regulate and arrest axis extension.
Introduction
Vertebrate embryos display a highly characteristic spatial patterning of tissues, including the arrangement of the neural tube, the somitic mesoderm and the notochord along the rostrocaudal (head-tail) length of the body axis (Fig. 1). Not only is this overall arrangement conserved, but the manner in which these axial tissues are produced is similar across vertebrate species. Much of the early patterning of the embryo is orchestrated during gastrulation by signals from a midline structure, known as the primitive streak in chick and mouse embryos. The postcranial axis (i.e. tissue caudal to the head) is then generated over an extended period in a rostral-to-caudal sequence by cells that are derived from the primitive streak and the adjacent epiblast cells, which together eventually form the tail bud. The area encompassing the primitive streak and the adjacent epiblast, and the later-forming tail bud, are the source of the neural tube and mesoderm over the entire period of body axis elongation (Fig. 2).
Detailed lineage analysis and fate-mapping studies have revealed that
subdomains exist within these primordia. The primitive streak in chick and
mouse embryos is organised such that the notochord emerges from its rostral
tip, known as the node, and more caudal portions of the streak generate
successively more lateral mesodermal tissues
(Cambray and Wilson, 2002
;
Psychoyos and Stern, 1996;
Selleck and Stern, 1991;
Wilson and Beddington, 1996).
A region that comprises the caudal end of the node and the rostral 5-10% of
the primitive streak has been termed the `axial-paraxial hinge', or `region C'
in chick (Charrier et al.,
1999), and the `node-streak border' in mouse
(Cambray and Wilson, 2002;
Cambray and Wilson, 2007).
Cells from this region contribute to the neural tube and the somites, as well
as to the notochord. Here, we will use the term `node-streak border' (NSB) to
refer to this cell population (Fig.
2A,B). The ventral midline of the neural tube is produced
exclusively by the dorsal part of the node
(Charrier et al., 1999;
Selleck and Stern, 1991). The
progenitors of the lateral and dorsal neural tube, and of some somitic tissue,
are found in an arc of epiblast tissue on either side of the primitive streak.
These progenitors have a rostral limit at the NSB and extend caudally for
about 50% of the length of the streak in chick at the 1- to 2-somite stage
(Brown and Storey, 2000;
Catala et al., 1996;
Schoenwolf, 1992;
Spratt, 1952), and for about
80% of streak length in mouse at the 2- to 6-somite stage
(Cambray and Wilson, 2007)
(Fig. 2A,B). This region has
been termed the caudal neural plate (Brown
and Storey, 2000), the stem zone
(Mathis et al., 2001) and the
lateral epiblast (Cambray and Wilson,
2007; Iimura and Pourquie,
2006). Here, we will refer to this region as the `caudal lateral
epiblast' (CLE), as it does not give rise to exclusively neural tissue and is
a caudally located epiblast cell population
(Fig. 2A,B). The spatial map of
prospective tissues in the tail bud is very similar to that in and adjacent to
the primitive streak in early (2-6 somite) embryos
(Fig. 2C-D'). In mouse
and chick, the derivative of the NSB (with a minor contribution from the CLE),
the `chordo-neural-hinge'(CNH) (Cambray
and Wilson, 2007; Catala et
al., 1995; Charrier et al.,
1999), contains progenitors for the ventral neural tube, somites
and notochord (Cambray and Wilson,
2002; McGrew et al.,
2008). The CNH is continuous with the most recently formed neural
tube and notochord (Fig.
2C-D'). By contrast, the tissue immediately caudal to the
CNH exclusively produces somites in mouse and chick
(McGrew et al., 2008).
As the body axis elongates, a transition occurs from primary neurulation,
during which the neural plate rolls up to form the neural tube, to secondary
neurulation, which occurs following the formation of the tail bud and which
involves the cavitation of a rod of tail bud mesenchyme. This switch indicates
a significant change in the cellular and molecular mechanisms that operate in
trunk and tail regions, and occurs at different times during axis extension in
chick and mouse embryos: the tail bud arises at the 22-somite stage [Hamburger
and Hamilton stage 14 (HH14)] in the chick
(Criley, 1969;
Hamburger and Hamilton, 1951)
and at the 30-somite stage [embryonic day 9.5-10 (E9.5-E10)] in the mouse
(Schoenwolf, 1984). However,
many reports also suggest that a set of stem cells generates axial tissues
(neural tube, somites, notochord) in these organisms. These cells are proposed
to reside in the primitive streak region, and to be incorporated into the tail
bud at a later stage of development. The self-renewing nature of stem cells
implies that the axial tissues produced by such cells would be generated in a
single continuous process rather than by separate cell populations (see
Fig. 3). Here, we consider the
accumulating evidence for the presence, persistence and multipotency of
self-renewing stem cells during the elongation of the mouse and chick body
axis and, crucially, identify equivalent cell populations in these two
animals. We further review the molecular characteristics of cells in regions
likely to contain such axial stem cells and the signalling pathways that
regulate their behaviour, including signalling changes that lead to the arrest
of body axis extension and to the determination of body length. Finally, we
discuss the evidence for the existence of axial stem cells in fish and frog,
and for the conservation of signalling mechanisms across species.
Evidence for the stem cell origin of axial tissues
Stem cells are classically defined by two characteristics: the ability to self-renew, giving rise to exact copies of themselves, and the capacity to give rise to one or more differentiated cell types. For a putative axial stem cell, self-renewal implies retention in the progenitor region throughout axial elongation. An axial stem cell must meet two additional criteria: (1) individual cells should normally contribute descendants to both rostral and caudal regions of the axis in vivo; and (2) the cells at late developmental stages should retain the capacity to generate rostral tissues as well as the caudal ones that they are normally fated to produce. Importantly, neither of these tests requires that the putative stem cells be multipotent. In principle, non-stem cell progenitors could be multipotent, and stem cells could contribute to single or multiple lineages.
|
). These studies revealed that single cells in the
node contribute in a periodic fashion to the notochord with an interval of two
somite lengths (Selleck and Stern,
1992; Selleck and Stern,
1991). This periodicity might be accounted for by a stem cell that
divides in the node at intervals to generate daughter cells that then
contribute to the notochord (Selleck and
Stern, 1992; Selleck and
Stern, 1991). Indeed, a rostrally located cell cluster in the
notochord has more cells and is less heavily labelled than the next (more
caudally located) cluster. This is consistent with each cluster being derived
from a single stem cell daughter, where rostral clusters have had more time to
divide than their later-born, more caudal, siblings. However, it should be
noted that although regular stem cell divisions could produce such a pattern,
this is not the only possible means by which a reiterated pattern of cell
contribution could be generated. For example, a population of labelled cells
might undergo a stereotyped pattern of intercalation with unlabelled cells.
Furthermore, such a pattern is not a prerequisite for these clusters having a
stem cell origin: variations in stem cell cycle time, periods where a given
stem cell does not contribute cells to the axis, and irregular patterns of
cell division in transient amplifying populations could all produce
distortions in a regular contribution pattern from stem cells.
|
). Live imaging of single cells in the chick CLE at stages
later than 10 somites (Mathis et al.,
2001) did reveal that, over a short culture period, some daughter
cells remained resident in this region, whereas others contributed to the
elongating neural axis (Mathis et al.,
2001). In the early mouse embryo, studies have also identified
cells in the rostral tip of the primitive streak that remain in the node after
a period of embryo culture (Forlani et
al., 2003; Lawson et al.,
1991). However, owing to the short culture periods employed in
these experiments, they do not address the question of whether cells reside in
the node for the whole period of axial elongation.
The first indication that some axial progenitors must persist over long
periods of time was inferred from retrospective clonal analyses of the mouse
myotome (the muscle progenitor compartment of the somite)
(Nicolas et al., 1996) and
spinal cord (Mathis and Nicolas,
2000). These studies exploited a modified form of the
lacZ reporter gene, termed laacZ, which contains a
duplication in its coding sequence, resulting in a truncated, non-functional
β-galactosidase protein. Reversion to functional lacZ occurs at
random, thus labelling individual revertant cells and their descendants and
allowing the visualisation of clones generated in vivo over the whole period
of axial elongation. By using laacZ under the control of a
myotome-specific or a neuronal-specific promoter, the patterns of cell
division that generate these tissues have been deduced. In the myotome, clones
that contribute to an axial length greater than seven somite segments (`long'
clones) have a rostral limit anywhere along the axis, but tend to continue as
far as the most caudal limit of promoter activity, indicating that they were
generated by cells that contributed to myotomes in a stem cell-like manner
(Nicolas et al., 1996) (see
Fig. 4A,B). This class of clone
has also been visualised in the neural tube, but fewer of these clones were
obtained and therefore this stem cell contribution pattern, in which large
clones extend to the caudal region, was less obvious
(Mathis and Nicolas, 2000). It
is, however, important to note that the promoters in these studies drive
expression in specific lineages (myotomal or neuronal); hence, these data
provide no information about the putative multipotency of such axial stem
cells.
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)
reveals that, although long clones display a strong tendency to contribute
from a variable rostral limit up to as far as the caudal end of the embryo,
several long clones do not fit this pattern, but stop well short of the caudal
end (Fig. 4C,D). Such clones
might arise in several ways. As the authors suggest, developmental variability
between litters leads to a different total number of somites in which the
promoter is active. However, several other possibilities could also explain
this result: (1) because the myotome progenitors in the tail bud were not
labelled in this study, the lack of caudal labelling might in reality
represent a very large unlabelled gap that indicates erratic stem cell
contribution; (2) not all long-clone progenitors are stem cells; or (3)
individual stem cells may exit the stem cell compartment. The limitations of
the study, namely the use of a tissue-specific promoter (which precludes
visualisation of the progenitors) and the relatively small number of long
clones, do not allow for the exclusion of any of these possibilities.
Therefore, even though some long clones support the existence of persisting
stem cells that contribute along the entire rostrocaudal length of the axis,
these studies leave open the possibility that not all axial cells derive from
stem cells.
A more recent study of laacZ-revertant clones in the spinal cord
further indicates that different contribution patterns characterise the
rostral and the caudal regions of this tissue
(Roszko et al., 2007). In
this study, the pattern of clones observed in the spinal cord caudal to somite
20 fitted well with a constant probability of labelling a given rostrocaudal
domain, which was interpreted as an indication of stem cell activity. By
contrast, the greater and less regular intervals between labelled cells that
were evident within clones in rostral regions suggested that other mechanisms
might operate here. These might include a non-stem cell mechanism, such as the
intercalation of existing short-term progenitors, but this pattern does not
necessarily exclude that a stem cell mechanism generates the rostral spinal
cord, which then undergoes differential growth after cells have exited the
stem cell compartment. Conversely, as noted above, a reiterative pattern of
contribution is not necessarily diagnostic of a stem cell contribution. This
study does, however, highlight that different mechanisms operate in the
rostral and caudal spinal cord, and raises the possibility that stem cells
might make different contributions to axial extension in distinct rostrocaudal
regions.
Although these retrospective lineage studies indicate that the progenitors
of the myotome and possibly also of the spinal cord are generated by stem cell
divisions, they do not provide information on where such cells are located or
on whether cells in the tail bud retain the capacity to contribute to rostral
axial levels. Tam and Tan (Tam and Tan,
1992) showed that cells in the mouse tail bud, when transplanted
to earlier primitive streaks, could contribute to axial tissues. In addition,
Cambray and Wilson (Cambray and Wilson,
2002) showed that the only progenitors that could contribute over
long axial distances in this assay were those in the CNH. Groups of
CNH-derived cells could be passaged through multiple primitive streaks and
still retain the capacity to contribute to both mesodermal and neural tissue
over long distances, with some cells remaining in the CNH. More recently,
another study (McGrew et al.,
2008) has demonstrated the same property for chick CNH cells.
Furthermore, this study has shown that cells caudal to the CNH in the tail bud
in both mouse and chick could contribute to somites over long axial distances,
but, unlike cells from the CNH, these could not be serially passaged. This
demonstrates that CNH cells are unique in their ability to contribute to axial
tissues over an extended period of time. It is, however, crucial to bear in
mind that all of these studies were performed using groups of cells, and
currently no study directly links the cells that can be experimentally
manipulated to behave like stem cells to the stem cell-like progenitors
identified by the retrospective lineage analyses.
Evidence for multipotency in axial stem cells
The clonal studies described above that indicate the existence of axial
stem cells do not provide information about the potency of these progenitors
– such cells might be separate neural and mesodermal progenitors or
multipotent cells. Selleck and Stern showed in the chick that single node
cells could contribute to more than one tissue (somite and notochord, or
notochord and ventral neural tube/floor plate)
(Selleck and Stern, 1991),
demonstrating that at least some cells in the region where stem cells are
predicted to reside are multipotent. Single-cell labelling of the mouse node
region between late-streak and head-fold stages also indicates that some cells
can contribute to the neural tube and somites, or to the notochord and somites
(Forlani et al., 2003).
Similar neural and somitic contributions were also observed by focally
labelling up to three epiblast cells close to the chick node
(Brown and Storey, 2000). It
is important to note that in all prospective clonal labelling studies, only a
small proportion of the total cells in the region of interest is labelled, and
the accuracy of the single-cell labelling technique used prior to culture is
often not reported. Reports of multipotency in progenitors must therefore be
interpreted and generalised with caution, and ideally should be confirmed by
more than one independent labelling method. However, the independent
observations of the presence of apparently multipotent cells in the node and
caudal lateral epiblast by several investigators
(Brown and Storey, 2000;
Forlani et al., 2003;
Lawson et al., 1991;
Selleck and Stern, 1991)
indicate that at least some progenitor cells are multipotent.
|
).
This, however, might be because too few cells were labelled, because a
dilution of dye occurred following multiple cell divisions, or because axial
stem cells arise later in this cell population. Evidence that supports this
latter possibility comes from the change in the contribution pattern of
labelled cells in different rostrocaudal regions of the spinal cord, as
revealed by the previously mentioned retrospective labelling study
(Roszko et al., 2007). A mixed origin for axial tissues
Whereas the data discussed above indicate where axial stem cells might
reside, fate-mapping studies during early gastrulation stages in both mouse
and chick show that there is a net movement of epiblast cells towards the
primitive streak, with most cells passing through this region and with few
epiblast cells apparently residing there
(Joubin and Stern, 1999;
Lawson et al., 1991;
Lawson and Pedersen, 1992;
Psychoyos and Stern, 1996;
Quinlan et al., 1995;
Tam, 1989). At least some of
these lateral epiblast cells appear to have an origin that is distinct from
the putative stem cells in the early gastrulation epiblast
(Hatada and Stern, 1994;
Lawson et al., 1991;
Tam, 1989). This is difficult
to reconcile with a model in which stem cells are the sole contributors to
axis elongation. Furthermore, it is noteworthy that cells transit through the
chick organiser region before the head process forms
(Joubin and Stern, 1999), but
that this net flow then ceases, just as the CLE becomes molecularly distinct
(see below), which raises the possibility that a suitable niche for resident
axial stem cells arises at this point. When traced from about this time, there
is also evidence that medial somite progenitors, which are initially located
in the NSB region, are retained in the later tail bud, whereas lateral somite
progenitors are cleared from this region after two days
(Iimura et al., 2007). This
latter work corroborates previous studies which also suggested that medial,
but not lateral, somite components have a stem cell origin
(Selleck and Stern, 1991;
Freitas et al., 2001)
(reviewed by Tam and Trainor,
1994). Hence, it is possible that the medial, but not the lateral,
somite component originates from stem cells.
In conclusion, even though there is compelling evidence that axial stem cells exist in both the mesodermal and neural lineages, the definitive identification of such cells requires further single-cell analysis to demonstrate both the ongoing contribution of individual cells to axial tissues and their long-term residence in the CLE/NSB and tail bud/CNH. These experiments should establish whether all, or merely some, axial tissue is derived from a stem cell population, and whether this corresponds to the multipotent cells observed at earlier stages. In particular, the use of a ubiquitously expressed promoter that drives laacZ would provide robust evidence for the existence of long-lived multipotent axial stem cells that can contribute to both mesodermal and neural lineages.
Axial stem cells and extension in lower organisms
The strong evidence that stem cells contribute to axial elongation in mouse
and chick, and the conservation of the vertebrate body plan suggest that this
mechanism should be conserved between vertebrates. However, reports in fish
and amphibians do not usually invoke stem cell participation in axis
development. Iimura and Pourquié have proposed that the separate origin
of medial and lateral somites is, in fact, conserved amongst all vertebrate
model organisms (Iimura and
Pourquié, 2007). Clonal lineage analyses in zebrafish and
Xenopus consistently show that cells close to or overlapping with the
organiser (the equivalent of the node) contribute to mostly medial regions of
the somites all along the axis, whereas cells progressively more distant from
the organiser contribute to successively more caudal somites and to more
lateral regions of the somite (Dale and
Slack, 1987; Hirsinger et al.,
2004; Keller,
1976; Kimmel et al.,
1990; Lane and Sheets,
2000). Therefore, it is plausible that in all vertebrates, both
organiser cells (i.e. putative stem cells) and separate populations of cells
distant from the organiser contribute to somitic tissue. Organiser-derived
somite cells constitute a minority population and thus may have been largely
overlooked in lower vertebrates.
A discrepancy between higher and lower vertebrates exists, however, in that
in Xenopus and zebrafish, the rostrocaudal differences in somite
contribution from cells originating near to and far from the organiser are
very large and are initiated very early: in these organisms, it is possible to
label cells at pre-gastrulation stages that will only contribute to the caudal
trunk and tail (Dale and Slack,
1987; Kimmel et al.,
1990). In mouse and chick, by contrast, the rostrocaudal offset
between labelled cell contribution to medial and lateral somite regions that
results from labelling cells close to and distant from the organiser
represents only a few somite lengths and can be detected only when cells are
labelled after the end of gastrulation
(Cambray and Wilson, 2007;
Iimura and Pourquie, 2006).
Furthermore, in chick and mouse, cells in the pre-gastrulation embryo do not
contribute exclusively to caudal, rather than rostral, somites. The exclusive
contribution of ventral cells to the caudal somites in fish and frog might
therefore reflect a much earlier specification of these cells in lower than in
higher organisms.
Because, as discussed above, there is evidence for multipotent cells in the
region of the organiser, it is of interest to establish whether fate maps of
the organiser in lower vertebrates also indicate the presence of multipotent
somite, notochord or neural cells. In zebrafish, the fate mapping of
single-cell progenitors of the caudal body shows that both the dorsal and
ventral components of the shield (the zebrafish equivalent of the node)
contribute to the tail somites, but that only the dorsal component produces
descendants in the spinal cord and notochord
(Kanki and Ho, 1997).
Interestingly, no single cell contributes descendants to more than one tissue
type. It is possible, however, that multipotent progenitors were missed in
this study owing to the small sample of cells labelled (n=105), or
that the location of the labelled cells did not coincide with mixed-fate
progenitors. Clonal labelling of cells at earlier gastrulation stages in the
organiser produced a small minority of multipotent cells
(Kimmel et al., 1990;
Melby et al., 1996). A
fate-mapping study using focal labelling
(Davis and Kirschner, 2000) in
Xenopus also suggests that some cells in the later CNH may be
multipotent. However, this result must be interpreted with caution, as up to
three cells were labelled per embryo, and therefore apparent multipotency may
result from the labelling of individual progenitors of restricted potency.
Hence, in contrast to mouse and chick, there is little definitive evidence to
support the presence of multipotent progenitors in Xenopus and
zebrafish any later than early gastrulation.
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The analysis of gene expression patterns in the primitive streak, the
caudal lateral epiblast and in the tail bud has identified many genes that
mark distinct subpopulations of cells from late gastrulation, as the head
process emerges and somitogenesis commences, until tail bud stages in both
mouse and chick (see Fig. 5). A
group of primitive streak marker genes, including fibroblast growth factor 8
(Fgf8) and Wnt3a, are expressed in the primitive streak, in
the upper (epiblast) layer of the NSB and in the CLE from late gastrulation
stages in mouse and chick embryos (Fig.
5A,B); these genes are also expressed in the tail bud
(Fig. 5A,B)
(Cambray and Wilson, 2007;
Chapman et al., 2002;
Gofflot et al., 1997) (K.G.S.
and I.O.-M., unpublished). The boundary between the rostral part of the node
and the NSB is marked in mouse by a transition in the epiblast domain between
a region of Fgf8 expression and an epiblast-specific expression
domain of the forkhead transcription factor Foxa2
(Fig. 5A), which might mark the
beginning of floor plate formation. Interestingly, in chick, the Fgf8
expression domain appears to extend further rostrally into the node itself and
overlaps with the epiblast-specific Foxa2 domain
(Fig. 5B). Hence, although the
expression of key marker genes in early caudal progenitor and tail bud cell
populations is conserved, there are some species-specific differences in the
precise spatial relationship of these genes.
The CLE becomes molecularly distinct from the rest of the neural plate as
the head process and the notochord emerge from the node at the 1- to 2-somite
stage. In the chick, this is indicated by the expression of the basic
helix-loop-helix (bHLH) proneural gene homologue Cash4 and an Nkx
transcription factor, Sax1
(Henrique et al., 1997;
Spann et al., 1994).
Sax1 expression is conserved in the mouse (Nkx1-2 –
Mouse Genome Informatics) and similarly distinguishes the CLE from rostral
neural plate regions (Schubert et al.,
1995). Unlike the rest of the neural plate, the CLE cell
population expresses both early pan-neural genes, such as Sox2, and
brachyury (T), which marks prospective as well as nascent paraxial
mesoderm (Cambray and Wilson,
2007; Delfino-Machin et al.,
2005; Kispert and Herrmann,
1994; Kispert et al.,
1995). In both chick and mouse embryos, this overlap between early
neural and mesodermal genes persists into tail bud stages and includes cells
in the CNH (Cambray and Wilson,
2007; Kispert and Herrmann,
1994; Kispert et al.,
1995; Knezevic et al.,
1998; Schubert et al.,
1995; Spann et al.,
1994). These expression patterns are therefore consistent with the
cell labelling studies described above, which indicate that the CLE
contributes to neural and mesodermal lineages, and with the possible existence
of multipotent neural and/or mesodermal axial stem cells in the caudal lateral
epiblast/upper layer of the NSB and the CNH.
Importantly, although there are many similarities between gene expression
patterns in the caudal lateral epiblast/NSB and the tail bud, they should not
be viewed as being exactly equivalent. The primitive streak does not express
caudal Hox genes, whereas the tail bud does. McGrew and colleagues showed that
Hoxa10, expressed in the tail bud, is dramatically downregulated a
few hours after tail bud cells are transplanted to the primitive streak of
earlier stage embryos, which are Hoxa10 negative
(McGrew et al., 2008).
Hoxa10 and Hoxc10 then become appropriately expressed as the
cells contribute to the axis. Thus, not only do CLE/NSB and tail bud cells
change their Hox gene expression profile over time, but these axial
progenitors retain the capacity to adapt this profile to more rostral and
developmentally younger environments, indicating that, at least for these
caudal-most Hox genes, the change in expression is a reversible process. These
findings underscore the general observation that the signalling environment
that progenitor cells experience influences their pattern of gene
expression.
Signals promoting body axis extension
Despite these differences in signalling environment across developmental
stages, the activity of a number of signalling pathways, including that of the
FGF, Wnt and Notch pathways, is known to maintain the undifferentiated cell
state of progenitors in the caudal region. Principal among these is FGF
signalling, and numerous FGFs are expressed in chick and mouse embryos in the
rostral primitive streak, in the CLE and in the presomitic mesoderm
(Boettger et al., 1999;
Crossley and Martin, 1995;
Karabagli et al., 2002;
Mahmood et al., 1995;
Ohuchi et al., 2000;
Riese et al., 1995;
Shamim and Mason, 1999). The
emergence of the presomitic mesoderm from the primitive streak is important
for the maintenance of Cash4 and Sax1, as the expression of
these genes is lost on the removal of this mesoderm in the chick
(Diez del Corral et al.,
2002), and mice that lack paraxial mesoderm owing to a mutation of
T also lose Sax1 expression
(Schubert et al., 1995). FGF
signalling maintains the expression of these genes in the CLE
(Diez del Corral et al., 2002;
Henrique et al., 1997), and a
direct requirement for FGFR signalling for Sax1 expression in these
epiblast cells has been demonstrated
(Delfino-Machin et al., 2005).
FGF signalling is also required for the movement of epiblast cells through the
primitive streak to form paraxial mesoderm
(Ciruna and Rossant, 2001;
Partanen et al., 1998;
Yamaguchi et al., 1994;
Yang et al., 2002) (see
Table 1). Fgf8
expression is downstream of Wnt3a
(Aulehla et al., 2003) in the
mouse, and Fgfr1 and Wnt3a mutant mice both form ectopic
neural tissue at the expense of paraxial mesoderm
(Takada et al., 1994;
Yamaguchi et al., 1994;
Yamaguchi et al., 1999b;
Yoshikawa et al., 1997) (see
Table 1), which is consistent
with the possibility that these tissues arise from a common progenitor. These
observations, together with the finding that low-level FGFR signalling
promotes neural cell fate in the Xenopus embryo
(Delaune et al., 2005;
Launay et al., 1996;
Linker and Stern, 2004;
Sasai et al., 1996), support
the idea that high levels of or prolonged exposure to FGF signalling promotes
mesoderm formation, whereas low levels elicit a neural fate (reviewed by
Stern, 2005). Interestingly,
it is the epiblast cells closest to the primitive streak that actively
transcribe Fgf8, whereas only mature Fgf8 mRNAs are detected
in the caudal paraxial mesoderm (Dubrulle
and Pourquié, 2004). The CLE might therefore be a region of
heightened FGF signalling – as further supported by high levels of
Erk1/2 mitogen-activated protein kinase activity
(Corson et al., 2003;
Lunn et al., 2007) –
that can provide a suitable niche for multipotent stem cells, which might
contribute to neural or mesodermal lineages. Neural progenitors might be
exposed to lower levels of FGF signalling for shorter time periods, exiting
the NSB/CLE for the neuroepithelium and downregulating Fgf8 (the loss
of which is promoted by retinoid signalling, see below), whereas cells
ingressing through the primitive streak continue to be exposed to high levels
of Fgf8 for longer, and hence give rise to mesoderm
(Fig. 6).
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)
(Fig. 6), although this
regulatory relationship does not appear to exist in the mouse caudal paraxial
mesoderm (Wahl et al., 2007).
In chick, Notch signalling in this medial part of the CLE is required to
maintain cell proliferation, and this role is also consistent with the axial
truncation that is seen in many mouse mutants that lack Notch signalling [such
as in Delta-like 3, Notch 1, Rbpj and lunatic fringe (Lfng) mutants]
(de la Pompa et al., 1997;
Donoviel et al., 1999;
Evrard et al., 1998;
Shen et al., 1997;
Wong et al., 1997) (see
Table 1). Other signals have
also been shown to maintain cell proliferation in caudal regions. Wnt5a acts
in the paraxial mesoderm and the primitive streak, but through a distinct
mechanism that does not involve conventional or canonical Wnt signalling
(Yamaguchi et al., 1999a).
Interestingly, Wnt5a mutants, like those of Wnt3a, fail to extend the tail
after E10.5 (Table 1), but
segmentation continues into their tail tip, as if the embryo simply failed to
form enough mesoderm rather than switching to a neural fate, as occurs in
Wnt3a mutant mice (see Table
1).
The findings discussed above suggest that a combination of FGF, Wnt and
Notch signalling acts to promote proliferation and to support the
less-differentiated cell state that is characteristic of tail end tissues.
Furthermore, differential exposure to Wnt/FGF signalling at the tail end might
additionally help to resolve neural and mesodermal cell fates in the extending
axis. Retinoid signalling is also implicated in this process, as excess
retinoic acid (RA) at the tail end not only causes axis truncation (see
below), but also generates a phenotype similar to that of Wnt3a mutant mice,
with neural tissue forming at the expense of paraxial mesoderm
(Abu-Abed et al., 2001;
Sakai et al., 2001). As cells
leave the tail end of the embryo, an attenuation of FGF signalling is required
for the onset of expression of differentiation genes in both neural and
paraxial mesodermal tissue (Diez del
Corral et al., 2003; Dubrulle
et al., 2001). The progressive loss of FGF signalling as cells
leave the caudal paraxial mesoderm is thought to constitute a wave-front,
which, in combination with the Notch-mediated periodic expression of so-called
`clock genes', determines the position of somite boundaries in this tissue
(for a review, see Dequeant and
Pourquié, 2008).
|
The arrest of body axis elongation seems intimately associated with the
differentiation process, as both involve the downregulation of FGFs and Wnts.
A key signalling pathway that regulates both processes is that mediated by RA.
During somitogenesis stages, cells are exposed to endogenous RA as they leave
the CLE and the NSB or later tail bud. This is provided by the activity of the
RA synthesising enzyme Raldh2, which is expressed in the newly
segmenting mesoderm. RA signalling drives the expression of neural and
mesodermal differentiation genes in axial tissues
(Diez del Corral et al., 2003;
Molotkova et al., 2005;
Moreno and Kintner, 2004;
Ribes et al., 2008). This
includes neuronal differentiation genes, which promote neuron production, the
floor-plate expression of sonic hedgehog (Shh), the key orchestrator
of ventral patterning and hence of neuronal cell-type specification
(Diez del Corral et al.,
2003), and mesodermal differentiation genes such as
Mesp2, a key segmentation gene that helps to define new somite
borders (Morimoto et al.,
2005).
RA promotes differentiation in part by inhibiting Fgf8 expression
as cells move out of the CLE and the primitive streak in chick and mouse
embryos (Diez del Corral et al.,
2003; Sirbu and Duester,
2006; Vermot et al.,
2005). It can also accelerate Fgf8 loss in the chick
caudal presomitic mesoderm (Diez del
Corral et al., 2003), where Fgf8 mRNA is not actively
transcribed (Dubrulle and Pourquie,
2004). This action thus also implicates RA signalling in the
paraxial mesoderm in the positioning of the somite boundary and hence in
determining somite size, given that the distance travelled by the falling
level of Fgf signalling in the presomitic mesoderm during one oscillation of
the segmentation clock defines where each somite boundary will form
(Dubrulle et al., 2001)
(reviewed by Dequeant and Pourquié,
2008). Consistent with this role, smaller (recently formed)
somites are found in retinoid-deficient animals
(Diez del Corral et al.,
2003). However, in later-stage mouse embryos, retinoid signalling
is not detected in the presomitic mesoderm and might only be required for
early segment formation in this context
(Sirbu and Duester, 2006). In
mice, Fgf8 is maintained by Wnt3a
(Aulehla et al., 2003), and in
chick Fgf8 in turn promotes the expression of Wnt8c (the orthologue
of mouse Wnt8a) in the forming neural axis
(Olivera-Martinez and Storey,
2007). The expression of all three genes is lost upon RA exposure
in both chick (Diez del Corral et al.,
2003; Dupe and Lumsden,
2001; Olivera-Martinez and
Storey, 2007) and mouse
(Iulianella et al., 1999;
Niederreither et al., 2000;
Shum et al., 1999) (see below
and Fig. 6).
Normally, the embryo deploys a number of mechanisms to protect the tail end
from retinoid signalling. The ones uncovered so far are all downstream effects
of FGF signalling (see Fig. 6).
FGF signals inhibit the onset of Raldh2 expression in the paraxial
mesoderm (Diez del Corral et al.,
2003) and also repress the expression of retinoic acid receptor
β (Rarb) in the neuroepithelium
(Olivera-Martinez and Storey,
2007). In addition, conditional Fgfr1 loss in the
T-expressing domain results in the loss of a major RA-metabolising
enzyme called Cyp26a, which is expressed at the mouse tail end
(Abu-Abed et al., 2001;
Sakai et al., 2001;
Wahl et al., 2007). This
regulatory relationship is conserved in Xenopus
(Moreno and Kintner, 2004).
Furthermore, in zebrafish, Notch signalling is upstream of Cyp26a
expression in the tail bud (Echeverri and
Oates, 2007). Crucially, the loss of Cyp26a (a cytochrome P450
oxidoreductase), of Por (a cytochrome P450 reductase, which donates electrons
to P450 enzymes during the breakdown of RA) or of germ cell nuclear factor
(Gcnf), also known as retinoid receptor-related testis-associated receptor
(RTR or Nr6a1; a mediator of retinoid signalling in ES cells), all lead to
axial truncations in the mouse (Abu-Abed et
al., 2001; Chung et al.,
2001; Gu et al.,
2005; Otto et al.,
2003) (see retinoid signalling mutants in
Table 1).
Significantly, and consistent with the above phenotypes, exposure to
exogenous RA causes axial truncations in many vertebrate embryos, including
the mouse (Griffith and Wiley,
1991; Kessel,
1992). This involves the rapid inhibition of Wnt3a
(Shum et al., 1999). Indeed,
the mouse mutant vestigial tail, which is a Wnt3a hypomorph, displays
caudal agenesis (Greco et al.,
1996; Gruneberg and
Wickramaratne, 1974; Takada
et al., 1994; Yoshikawa et
al., 1997), and both RA-treated embryos and vestigial tail mutants
exhibit extensive cell death in the tail bud
(Shum et al., 1999) (see
Table 1). Wnt3a and
Fgf8 expression can both promote the expression of the transcription
factor T (Galceran et al.,
2001; Yamaguchi et al.,
1999b). T mutant embryos also exhibit dramatic axial
truncation (Chesley, 1935)
(see Table 1). This can be
rescued by the T gene in a dose-dependent manner
(Stott et al., 1993) and its
loss is also characterised by precocious cell death in the mouse primitive
streak (Chesley, 1935). Taken
together, these findings suggest that Wnt3a and Fgf8 signalling upstream of
T and Cyp26a expression promote cell survival in the tail
bud.
As the presomitic mesoderm shortens during axial elongation
(Gomez et al., 2008;
Sanders et al., 1986), RA
from the most recently formed somites might now be able to reach tail bud
cells, thereby ending this process. This possibility is supported by the
downregulation of Fgf8 in the mouse tail by E12.5
(Cambray and Wilson, 2007) and
in the chick at HH26/HH27 (I.O.-M. and K.G.S., unpublished) just prior to the
end of axis elongation. This might elicit a slowing down of the cell cycle and
the eventual cell cycle exit of progenitor cell populations. Conversely, the
loss of Fgf8 also coincides with high levels of cell death in the
late-stage chick tail bud (Hirata and
Hall, 2000; Mills and
Bellairs, 1989; Sanders et
al., 1986; Yang et al.,
2006), raising the possibility that a local increase in endogenous
RA triggers apoptosis to terminate axis extension.
Although premature cell death can produce axial truncations, it is unlikely
to be the sole cause of this phenotype. Mice that lack the expression of the
transcription factors caudal type homeobox 1 (Cdx1) and Cdx2
have axial truncations similar to those seen in Wnt3a, Lef/Tcf1
double mutants (Galceran et al.,
1999), Fgfr1 hypomorphs
(Partanen et al., 1998) and
heretozygous T mutants (Herrmann
et al., 1990; van den Akker
et al., 2002) (Table
1). However, cell death does not appear to increase in the tail
bud of these embryos, although complete Cdx null mice have yet to be examined
(J. Deschamps, personal communication). Cdx genes are regulated by FGF and Wnt
in the chick caudal lateral epiblast
(Bel-Vialar et al., 2002;
Nordstrom et al., 2006;
Wang and Shashikant, 2007)
and have been proposed to regulate proliferation in this tail bud context
(van den Akker et al., 2002).
Indeed, an increased dose of Cdx2 protein also leads to axis truncation, but
in this case neurulation is defective and excessive mesodermal tissue forms in
a bulbous mass at the tail end, as if cells over-proliferate and fail to exit
this region to commence differentiation
(Gaunt et al., 2008). This
suggests that an imbalance between the maintenance of progenitors and their
differentiation might be an alternative cause of axial truncation.
Signals from the ventral ectodermal ridge (VER), an ectodermal thickening
that runs along the underside of the tail bud
(Gruneberg, 1956), are also
required for the normal elongation and segmentation of the tail
(Goldman et al., 2000;
Liu et al., 2004;
Ohta et al., 2007). However,
VER removal does not appear to induce cell death
(Goldman et al., 2000). The
VER maintains expression of the bone morphogenetic protein (BMP) antagonist
noggin (Nog) in the underlying tail bud mesenchyme
(Goldman et al., 2000), and
Nog mutant mice display axial truncations from E10.5
(McMahon et al., 1998)
(Table 1). These mutants lack
the VER and display neither cell death nor proliferation defects in the tail
bud (Ohta et al., 2007).
However, they do exhibit ectopic cell ingression from the outer ectoderm
mediated by BMP signalling (Ohta et al.,
2007). The VER therefore exerts its influence, at least in part,
by maintaining the correct level of BMP signalling. This seems to be crucial
for normal cell movements in the tail bud, which might be a further
requirement for normal axial elongation.
It will be interesting to discover how these different signalling pathways
act on distinct tail bud progenitor populations, and how they interact to
arrest axis extension and to define body length. The impact of these signals
on the expression of cell identity genes, including Cdx and Hox genes, such as
Hoxb13, the loss of which promotes excessive axis extension
(Economides et al., 2003),
will also further elucidate how positional identity is linked to cell
behaviour. Some of these signals that regulate body axis extension in chick
and mouse embryos are also implicated in the related process of tail induction
in lower vertebrates.
Conservation of signalling mechanisms regulating axis extension
The comparison of the regulation of axis extension in higher vertebrates
with tail induction in lower vertebrates might reveal evolutionarily conserved
mechanisms. Tucker and Slack proposed a model for tail development in
Xenopus in which the cells that remain in the blastopore (equivalent
to the primitive streak remnant) at the end of gastrulation are composed of
three separate populations that interact to initiate tail elongation: the
neural precursors in the neural plate (the N region); the muscle progenitors
immediately behind them in the ectoderm (the M region); and the underlying
notochord (the C region) (Tucker and
Slack, 1995). These three regions are then incorporated into the
CNH of the tail bud. The topological equivalent of the N-M-C junction would
therefore be the NSB in mouse and chick.
In zebrafish, blastopore closure has been proposed to bring the dorsal
cells (the organiser, expressing nodal-related genes and Bmp2/Bmp4
antagonists) close to the ventral involuting cells that express Bmp2/Bmp4
(Agathon et al., 2003). This
ventral tissue has a `tail organiser' activity, i.e. it promotes tail
outgrowth without contributing to all tail tissues through the combinatorial
activity of the BMP pathway with Wnt and Nodal signalling. This agrees with
data in Xenopus that show that BMP signalling is essential for tail
somitogenesis (Beck et al.,
2001), and that the induction of tail outgrowth requires Xwnt3A
(Beck and Slack, 2002). In the
zebrafish tail induction studies, FGF signalling was not specifically
investigated. In Xenopus, however, the species in which the
mesoderm-inducing properties of FGF signalling were first shown
(Slack et al., 1988),
blocking FGF signalling leads to axial truncations, showing that FGF is
involved in axial elongation (Amaya et al.,
1991). Furthermore, retinoid signalling also attenuates FGF
signalling in the frog body axis, supporting the idea of conservation of the
signalling mechanism that regulates differentiation onset during axis
elongation (Moreno and Kintner,
2004). Notch signalling is also important for Xenopus
tail bud outgrowth (Beck and Slack,
1999; Beck and Slack,
2002). Therefore, in all vertebrates studied, axial elongation
seems to involve similar signalling pathways. However, the N-M-C model for
tail bud induction in Xenopus is proposed to act at stage 13 (early
neurula stage), well before the beginning of somite segmentation at stage 17
(Hausen, 1991;
Nieuwkoop and Faber, 1967).
Similarly, in zebrafish, tail bud induction is proposed to take place at, or
just before, the onset of somitogenesis
(Kimmel et al., 1995), which
is essentially the equivalent of mouse late head-fold/early somite stage or
chick HH5-HH7. Therefore, the mechanisms that are proposed to induce the tail
in Xenopus and zebrafish might act at mouse and chick late primitive
streak stages, and it is possible that, in these organisms, they ensure
continued axis elongation during early somitogenesis stages rather than
producing the tail bud per se.
Interestingly, during node regression in the mouse, the node approaches the caudal end, such that once the tail fold is formed the ventral BMP-expressing tissue is closely apposed to the organiser. Therefore, the phase of somitogenesis that occurs after node regression in the mouse, i.e. the formation of the axis caudal to the forelimb bud, might depend on the close apposition of BMP, Wnt and Nodal signalling. Nodal expression completely disappears from the mouse axis by E9.5 (i.e. between the 8- and 22-somite stages) and is therefore unlikely to play a part in the formation of the post-anal tail. This lends further support to the idea that, if signalling mechanisms similar to those described above for lower vertebrates operated in chick and mouse, they would act not in the formation of the tail, but more rostrally in the axis.
Conclusions
The evidence discussed above suggests that vertebrate axis elongation is
likely to depend on contributions from a mixture of the output of a retained
stem cell population and of transient progenitors. This stem cell contribution
has only been studied in mesodermal and neural tissues, and the mechanism of
extension of the third germ layer, the endoderm, has received little
attention. Because all three layers extend along the whole axis, it is likely
that mechanisms exist to ensure their coordinated extension. This is supported
by the observation that in mouse mutants that display axial truncations (such
as the Cdx2 mutant)
(Chawengsaksophak et al.,
2004) gut endoderm fails to form from the same level as neural and
mesodermal tissues. However, evidence for a stem cell population in the tail
bud region effecting gut elongation is currently lacking. This is in part
because long-term clonal analysis has yet to be carried out in this tissue.
The extent to which axial stem cells contribute to body extension might vary
during the course of this process, and between higher and lower vertebrate
model embryos. It is now important to identify the precise location(s) and
molecular characteristics of the axial stem cell sub-population, as well as
the signalling niche that specifies and maintains this distinct cell type.
Current data suggest that these cells reside in the NSB, but possibly also at
the edge of the primitive streak in the CLE and in the later-forming CNH.
These cells might be maintained by a combination of high FGF, Wnt and Notch
signalling, and perhaps by the expression of P450 enzymes, such as Cyp26a,
which together promote proliferation, maintain an uncommitted progenitor cell
state and provide protection from retinoid-mediated differentiation. Axial
stem cells might share some properties with recently identified epiblast stem
cells derived from the pre-gastrula epiblast, which self-renew, in mouse, when
exposed to a combination of FGF and activin and, in human, in response to FGF
alone (Brons et al., 2007;
Rossant, 2008;
Tesar et al., 2007). A key
challenge for the future is to understand the essential changes that take
place as cells progress along the apparent continuum from an embryonic stem
cell to an epiblast stem cell-like state and, later, to a potential axial stem
cell state.
ACKNOWLEDGMENTS
We are grateful to Pamela Halley for cryostat sections of chick embryos and for the photographs shown in Fig. 5Bb-d,g-i, and to anonymous reviewers for helpful comments. V.W., K.G.S. and I.O.-M. are supported by the MRC. V.W. is also supported by the Association for International Cancer Research.
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