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First published online April 13, 2005
doi: 10.1242/10.1242/dev.01794
Review |
Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK
e-mail: c.stern{at}ucl.ac.uk
SUMMARY
During neural induction, the embryonic neural plate is specified and set aside from other parts of the ectoderm. A popular molecular explanation is the `default model' of neural induction, which proposes that ectodermal cells give rise to neural plate if they receive no signals at all, while BMP activity directs them to become epidermis. However, neural induction now appears to be more complex than once thought, and can no longer be fully explained by the default model alone. This review summarizes neural induction events in different species and highlights some unanswered questions about this important developmental process.
Introduction
During gastrulation, cells ingress from the surface ectoderm into the
interior of the embryo to give rise to the mesodermal and endodermal germ
layers. In vertebrates, ingression can occur through a blastopore (as in
amphibians), around and through an embryonic shield (as in teleosts), or
through a primitive streak (as in amniotes: reptiles, birds, mammals).
Dramatically, transplantation of the most-dorsal lip of the amphibian
blastopore to the ventral side (prospective belly) of another embryo at the
gastrula stage generates a second axis, in which almost all of the central
nervous system (CNS) (with the exception of regions of the floor plate) is
derived from the host ectoderm rather than from the graft. It was this
experiment, performed by Hans Spemann's student Hilde Mangold
(Spemann, 1921
;
Spemann and Mangold, 1924)
between differently pigmented species of newt, that firmly established the
concept of neural induction as an instructive interaction between the dorsal
lip of the blastopore (the `organizer') and the neighbouring ectoderm. This
instructive interaction leads to the induction of the nervous system. Soon
thereafter, the equivalent region was discovered in most vertebrate classes:
the shield of teleosts (Luther,
1935; Oppenheimer,
1936b) and Hensen's node (the distal tip of the primitive streak)
in birds and mammals (Waddington,
1932; Waddington,
1933; Waddington,
1936; Waddington,
1937). Each of these will induce a neural plate not only within
the same species but also when transplants are performed across classes (e.g.
Waddington, 1934;
Oppenheimer, 1936a;
Kintner and Dodd, 1991;
Blum et al., 1992;
Hatta and Takahashi, 1996),
strongly indicating that the mechanisms of neural induction are conserved
throughout the vertebrates.
A first molecular explanation: the default model
For more than six decades, many laboratories tried very hard to uncover the
molecular nature of the signals emitted from the organizer, always with the
expectation that a single molecule might be `the neural inducer'. This met
with little success, partly because in the newt, where most of the experiments
were carried out, many heterologous substances can generate ectopic neural
structures (reviewed by Nakamura and
Toivonen, 1978; Hamburger,
1988; Stern,
2004). The turning point only came in the mid-1990s, when several
groups made a number of observations that at first seemed unconnected. First,
it was observed that the dissociation of Xenopus gastrula-stage
animal caps into single cells for a short time before reaggregating them led
to the formation of neural tissue (Born et
al., 1989; Godsave and Slack,
1989; Grunz and Tacke,
1989; Sato and Sargent,
1989; Saint-Jeannet et al.,
1990). Then, it was found that misexpression of a
dominant-negative `activin' receptor (later discovered to inhibit several
TGFß-related factors) in Xenopus embryos blocked mesoderm
formation, but also unexpectedly generated ectopic neural tissue
(Hemmati-Brivanlou and Melton,
1992; Hemmati-Brivanlou and
Melton, 1994). These findings were later connected by the idea
that neural tissue might be induced by the removal of some unknown inhibitory
substance (Hemmati-Brivanlou and Melton,
1994). Soon, three genes encoding proteins with neuralizing
activity were isolated and found to be expressed in the organizer: Noggin
(Smith and Harland, 1992;
Lamb et al., 1993;
Smith et al., 1993;
Furthauer et al., 1999),
Follistatin (Hemmati-Brivanlou et al.,
1994) and Chordin (Sasai et
al., 1994; Sasai et al.,
1995). These turned out to be binding partners of bone
morphogenetic proteins (BMPs) that antagonize BMP signalling
(Piccolo et al., 1996;
Zimmerman et al., 1996;
Fainsod et al., 1997). That
the postulated inhibitory substance was BMP4 was also supported by the finding
that BMP4 is an effective inhibitor of neural fate while promoting epidermal
differentiation, even in dissociated cells
(Hawley et al., 1995;
Wilson and Hemmati-Brivanlou,
1995). These findings led to the `default model' of neural
induction (Hemmati-Brivanlou and Melton,
1997) (Fig. 1),
which proposes that cells within the ectoderm layer of the frog gastrula have
an autonomous tendency to differentiate into neural tissue, which is inhibited
by BMPs (in particular, BMP4, which acts as an epidermal inducer).
|
;
Suzuki et al., 1997b;
Wilson et al., 1997),
consistent with the view that neural fates are inhibited by an endogenous BMP
activity. Moreover, the expression pattern of Bmp4 in
Xenopus conforms to its proposed anti-neural function: in the early
gastrula, Bmp4 transcripts are widely expressed in the entire
ectoderm and then are lost from the future neural plate when the organizer
appears (Fainsod et al.,
1994). The transcription of BMP genes is maintained by the
activity of BMP protein (Biehs et al.,
1996; Schulte-Merker et al.,
1997). This accounts for the disappearance of Bmp4 and
Bmp7 expression from the vicinity of the organizer, the source of BMP
antagonists, at the late gastrula stage
(Fainsod et al., 1994;
Hawley et al., 1995;
Baker et al., 1999). Animal
caps cut from embryos injected with dominant-negative BMP receptors
(Sasai et al., 1995;
Xu et al., 1995), with
non-cleavable forms of BMP4 or BMP7
(Hawley et al., 1995), or with
antisense Bmp4 RNA (Sasai et
al., 1995) adopt a neural, rather than an epidermal, fate.
Finally, Chordin and Noggin proteins can neuralize isolated animal caps
(although this seems to work best if the animal caps are first exposed briefly
to a low Ca2+/Mg2+ medium - the rationale given for this
is that this treatment helps the protein penetrate between the cells)
(Lamb et al., 1993;
Sasai et al., 1995). Other
secreted, BMP-antagonizing molecules have been found that are expressed in the
organizer or in its proximity, such as Cerberus
(Bouwmeester et al., 1996;
Belo et al., 1997), Gremlin,
Dan and Drm (Hsu et al., 1998;
Pearce et al., 1999;
Dionne et al., 2001;
Eimon and Harland, 2001;
Khokha et al., 2003), and
Ogon/Sizzled (Wagner and Mullins,
2002; Yabe et al.,
2003b). Furthermore, depletion of three BMP antagonists (Chordin,
Noggin and Follistatin) from Xenopus tropicalis embryos using
morpholino oligonucleotides causes a dramatic ventralization of the embryo,
which includes almost complete loss of the neural plate
(Khokha et al., 2005).
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Is BMP inhibition sufficient for neural induction?
One might argue that the ideas of `default' and `sufficient' are
inappropriate terms to describe any biological process, mainly because both
concepts imply that the previous developmental history and present state of
the cell are unimportant. Not surprisingly, more recent research on neural
induction has started to uncover new players, as well as complex interactions
between them. A first challenge to the default model came from observations in
amphibian embryos, where it was found that neither Chordin
(Sasai et al., 1996) nor
Noggin (Launay et al., 1996)
could induce neural tissue in embryos in which FGF signalling had been blocked
by the injection of a dominant-negative FGF receptor. Further challenges to
the default model came from studies in chick embryos
(Table 1, Fig. 3). These studies reported
several key findings: that the expression patterns of BMPs and their
antagonists do not fit the default model, that misexpressing BMP antagonists
in competent epiblast does not induce the expression of any neural markers,
and that a grafted source of BMP protein does not inhibit neural plate
development (except for a slight narrowing of the neural plate)
(Streit et al., 1998;
Streit and Stern, 1999a;
Streit and Stern, 1999b).
Moreover, although both BMP4 mRNA and phospho-Smad1 (an effector of
BMP signalling) are downregulated in the forming chick neural plate
(Streit and Stern, 1999a;
Streit and Stern, 1999b;
Faure et al., 2002), this
occurs at a relatively late stage of development, when compared with the
timing of their downregulation in Xenopus, and only after the neural
plate markers SOX3 and SOX2 have begun to be expressed.
However, exposure of the chick epiblast to a grafted organizer for 5 hours
(11-13 hours are required for neural induction)
(Gallera and Ivanov, 1964;
Gallera, 1971) transiently
induces the early neural plate marker SOX3
(Table 2), the expression of
which can be stabilized by Chordin after removal of the grafted organizer
(Streit et al., 1998). This
finding implies that the ectoderm must be exposed for 5 hours to signals from
the organizer before it can respond to BMP antagonists.
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|
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),
and churchill, which is induced after 4-5 hours
(Sheng et al., 2003). Both
are expressed in the prospective neural plate, but neither is induced by BMP
antagonists, although both genes are induced by fibroblast growth factor
(FGF). In fact, inhibiting FGF signalling completely blocks neural induction
by a grafted node and in prospective neural plate explants
(Streit et al., 2000;
Wilson et al., 2000).
Consistent with these findings in chick, co-injecting either chordin
(Sasai et al., 1996;
Pera et al., 2003) or
noggin (Launay et al.,
1996) together with a dominant-negative FGFR1 construct into the
animal pole of Xenopus embryos does not lead to the neuralisation of
the animal caps taken from these embryos. This suggests that FGF signalling is
required for BMP antagonists to induce neural markers. The same conclusion was
reached more recently using a different approach
(Linker and Stern, 2004;
Delaune et al., 2005). In
these studies, the intracellular BMP antagonist Smad6 was injected into the
most-ventral blastomere (A4) of Xenopus embryos, the progeny of which
do not contribute to either the prospective neural plate or to its border.
This treatment was found to be insufficient to neuralise the descendants of
the injected cell unless FGF4 was co-injected with it.
A role for FGFs in neural induction
Strikingly in ascidians, which are basal chordates, FGFs, rather than BMP
inhibition, are the endogenous factors responsible for generating the nervous
system (Inazawa et al., 1998;
Darras and Nishida, 2001;
Hudson and Lemaire, 2001;
Kim and Nishida, 2001;
Bertrand et al., 2003;
Hudson et al., 2003). In
vertebrates, there has been more controversy about the role of FGFs in neural
induction. It has been claimed that FGFs can direct ectodermal cells to a
neural pathway in amphibians (Kengaku and
Okamoto, 1995; Lamb and
Harland, 1995; Hongo et al.,
1999; Strong et al.,
2000), zebrafish (Kudoh et
al., 2004) and chick
(Rodríguez-Gallardo et al.,
1997; Alvarez et al.,
1998; Storey et al.,
1998) in the absence of other signals. However, in
Xenopus, this activity requires special experimental conditions
(either partial dissociation of the cells or the isolation of animal caps)
(Pera et al., 2003;
Linker and Stern, 2004;
Delaune et al., 2005), while
in chick, the induced neural tissue is of a posterior character; whether or
not the induction is direct (without the prior induction of mesoderm and/or
endoderm) has not been firmly established. It is now generally believed that
FGFs are probably not direct neural inducers in vertebrates, or at least not
by themselves.
There has also been controversy concerning whether or not FGFs are required
at all for neural induction in amphibians. This is because the injection of
dominant-negative FGFR1 inhibits mesoderm formation and posterior axis
development but not neural induction (Amaya
et al., 1991; Cox and
Hemmati-Brivanlou, 1995; Kroll
and Amaya, 1996; Godsave and
Durston, 1997; Holowacz and
Sokol, 1999; Curran and
Grainger, 2000; Ishimura et
al., 2000; Ribisi et al.,
2000; Pownall et al.,
2003). However, it has been proposed that neural induction may
involve FGFR4 rather than FGFR1 (Hongo et
al., 1999; Hardcastle et al.,
2000; Umbhauer et al.,
2000), and a more recent study using a general inhibitor of FGFRs
has uncovered a clear requirement for FGF signalling in neural induction in
Xenopus (Delaune et al.,
2005). Overall, it is now generally accepted that FGF signalling
is required for neural induction both in amphibians
(Launay et al., 1996;
Sasai et al., 1996;
Xu et al., 1997;
Hardcastle et al., 2000;
Strong et al., 2000;
Pera et al., 2003;
Linker and Stern, 2004;
Delaune et al., 2005) and in
chick (Streit et al., 2000;
Wilson et al., 2000;
Linker and Stern, 2004).
Relationships between MAPK and BMP signalling in neural induction
To reconcile the default model with findings implicating FGFs in neural
induction (Fig. 4), it has been
proposed that the activation of MAP kinase (MAPK) by FGF [or by other factors
that activate this pathway, such as IGF (insulin-like growth factor) and Nodal
acting through its EGF-CFC co-factors] can inhibit the downstream targets of
BMP (Furthauer et al., 1997;
Wilson et al., 2000;
Bainter et al., 2001;
Pera et al., 2001;
Wilson and Edlund, 2001;
Wilson et al., 2001;
Koshida et al., 2002;
LeSueur et al., 2002;
Pera et al., 2003;
Yabe et al., 2003a) [see De
Robertis and Kuroda (De Robertis and
Kuroda, 2004) for a comprehensive review]. In particular, it has
been shown that FGF signalling can phosphorylate a linker region in the middle
of the BMP effector Smad1 (a modification that inhibits Smad1), whereas BMP
signalling causes the Smad1 C-terminal domain to be phosphorylated (which
activates it) (Pera et al.,
2003; De Robertis and Kuroda,
2004). This interesting finding greatly helps to explain some of
the apparently contradictory results in Xenopus. In agreement with
this, it has been reported that merely wounding an amphibian embryo can
activate MAPK (LaBonne and Whitman,
1997; Christen and Slack,
1999), which might partly account for the apparent `sufficiency'
of BMP inhibition for neural induction in animal cap assays
(Streit and Stern, 1999c).
However, three recent studies have suggested that FGF signalling is required
for neural induction independently of its ability to downregulate BMP targets
(Aubin et al., 2004;
Linker and Stern, 2004;
Delaune et al., 2005). Thus,
although one effect of MAPK signalling is to downregulate BMP signalling, this
function alone does not explain completely why FGF is required for neural
induction.
|
;
Furthauer et al., 2004;
Kudoh et al., 2004;
Rentzsch et al., 2004).
However, these experiments were conducted by injecting constructs at very
early stages of development, and it cannot be excluded that the induction by
either signal is indirect, that cell movement patterns are altered (causing
cells from the normal neural plate to be recruited into the ectopic neural
plate) or that each initiates a complex cascade of events that culminates in
ectopic neural marker expression, but only as a consequence of multiple
cooperating signals.
Does Wnt signalling play a role in neural induction?
In a second attempt to reconcile the default model with findings in the
chick, it has been proposed that two separate pathways are initiated by FGF:
one by which FGF induces neural fates independently of BMP inhibition; and
another through which FGF represses BMP transcription, a pathway that
additionally requires the inhibition of the Wnt pathway
(Wilson and Edlund, 2001;
Wilson et al., 2001)
(Fig. 4). In chick, the cells
of the prospective neural plate (the medial epiblast) would use predominantly
the first pathway, whereas the second pathway might coax prospective epidermis
(lateral epiblast) to acquire a neural fate. The evidence for this idea has
mainly come from experiments in which explants have been exposed to these
factors or to blocking reagents (see Table
1) (Wilson et al.,
2000; Wilson et al.,
2001). It has also been shown that Wnt antagonism can stimulate
neural differentiation in stem cells under certain conditions
(Aubert et al., 2002).
Conversely, another group has reported that neural induction in
Xenopus requires activation of the canonical (ß-catenin) Wnt
pathway, by showing that this pathway represses BMP expression
(Baker et al., 1999). These
apparently contradictory findings can be reconciled most easily by taking into
account differences in timing. At early stages of development, when the embryo
is acquiring dorsoventral polarity, Wnt signals are required to specify
`dorsal' character; the study of Baker et al.
(Baker et al., 1999) provides
an attractive mechanism by which Wnt signalling (a very early dorsal
determinant) controls the distribution of BMP activity (which is required for
the dorsoventral patterning of the embryo). By the blastula/early gastrula
stage, it may be necessary to inhibit Wnt signals for FGF to downregulate BMP
expression (Bainter et al.,
2001; Wilson and Edlund,
2001). Despite this, a recent study showed that even a combination
of FGFs (FGF2, FGF3, FGF4 or FGF8) together with the BMP antagonists Smad6,
Chordin and/or Noggin and three different Wnt antagonists, was still unable to
induce expression of the neural marker SOX2 directly in chick epiblast in
intact embryos (Linker and Stern,
2004). This finding strongly suggests that, in vivo, signals other
than FGF, BMP inhibition and/or Wnt inhibition are required for neural
induction, at least in the chick.
Other players: Ca2+ and PKC
In addition to the signals discussed above, many other proteins have been
implicated in neural induction (reviewed by
Stern, 2004); however, most
of them seem to act directly or indirectly by modulating BMP or MAPK
signalling. Apart from these, an intracellular rise in
Ca2+-mediated by L-type Ca2+ channels has been proposed
as a neural-inducing signal (Moreau et
al., 1994; Leclerc et al.,
1997; Leclerc et al.,
2003), although the possibility that it too regulates BMP
signalling or acts through the mesoderm has not been excluded
(Palma et al., 2001;
Leclerc et al., 2003).
Finally, the balance between protein kinase C (PKC) and cAMP
(Otte et al., 1988;
Otte et al., 1989;
Otte and Moon, 1992), which
does not seem to relate to the pathways of any of the known players, is a
possible signal that can trigger neural specification in amphibians.
Surprisingly, this has not been followed up and probably deserves more
attention.
In conclusion, therefore, findings from recent years have revealed more complexity in the mechanism of neural induction than has been proposed by the default model. Clearly, the initial hope that a single secreted factor might encapsulate all of the inducing and patterning activities of the organizer (dorsalization, neural induction and anteroposterior patterning) has all but vanished. One reason why it has been so difficult to identify the key players in this process is that embryos appear to generate complexity with only a handful of extracellular signals, each of which has multiple roles at different times in development. The use of assays limited to the misexpression of constructs only at early cleavage stages, followed by an analysis of the consequences only at a much later stage of development, will reveal the cumulative effects of the injected molecule for all stages previous to that being studied, including complex or unknown interactions with other pathways. To progress further, we need to know more about the embryological aspects of neural induction.
When does neural induction occur?
For timed misexpression experiments, it is essential to know when neural
induction normally occurs. However, it is not easy to determine which step in
a cascade represents the inductive event: is it the initial specification that
biases cells to their new fate, but does not irreversibly commit them, or is
it the final commitment step? It is therefore relatively easy to determine
when neural induction ends, but much more difficult to establish when it
begins. In the chick, carefully timed node transplantation experiments have
established that the node loses its inducing ability gradually, starting
immediately after stage 4 (full primitive streak stage, just before the
emergence of the head process; see Fig.
3). Competent regions of host embryos not fated to become neural
plate rapidly lose their ability to respond to a node transplant between
stages 4 and 4+, strongly suggesting that the induction of a
complete CNS by the organizer normally ends between these two stages
(Gallera and Ivanov, 1964;
Gallera and Nicolet, 1969;
Gallera, 1970;
Gallera, 1971;
Dias and Schoenwolf, 1990;
Storey et al., 1992;
Storey et al., 1995;
Streit et al., 1997;
Darnell et al., 1999).
Likewise, in amphibians, it is generally believed that the competence of the
ectoderm to respond to neural induction is lost at the end of the gastrula
stage, between stages 12 and 13
(Waddington and Needham,
1936; Gurdon,
1987; Sharpe and Gurdon,
1990; Servetnick and
Grainger, 1991). As for the start of the process, it has generally
been assumed that it begins at the early gastrula stage, as the organizer is
difficult to define before then. However, studies in chick embryos have
suggested that the earliest neural induction steps occur before the start of
gastrulation, are marked by ERNI and SOX3 expression, and
can be mimicked by, and require, FGF signalling
(Streit et al., 2000;
Wilson et al., 2000). Similar
conclusions have now been reached for amphibians
(Kuroda et al., 2004;
Delaune et al., 2005).
Sources of signals
If neural induction begins before gastrulation, when there is no
morphological organizer (Hensen's node or dorsal lip), what tissues emit the
inducing signals? Before chick gastrulation, FGF8 is expressed in the
hypoblast (which underlies the expression domains of SOX3 and
ERNI in the epiblast). Hypoblast tissue grafted to a remote region of
the chick embryo can induce the ectopic expression of these markers (as well
as of OTX2 and NOT1)
(Foley et al., 2000;
Streit et al., 2000;
Knezevic and Mackem, 2001) but
only transiently. However, there also appears to be some constitutive
expression of FGF3 in the epiblast itself
(Wilson et al., 2000). The
relative contributions of these factors to the normal expression of
SOX3 and ERNI have not been elucidated.
Hensen's node derives from two cell populations, the `posterior' and
`central' cells, that are present before gastrulation. The posterior cells lie
deep to the epiblast in the medial part of a crescent-shaped ridge of
middle-layer cells called Koller's sickle, which is situated at the posterior
edge of the embryo. These cells express chordin and
goosecoid
(Izpisúa-Belmonte et al.,
1993; Streit et al.,
1998; Streit et al.,
2000), and move anteriorly with the extending primitive streak
(Hatada and Stern, 1994;
Bachvarova et al., 1998;
Robb and Tam, 2004). Before
this stage, `central cells' are present in the epiblast and are defined as
being node progenitors by fate mapping
(Hatada and Stern, 1994;
Foley et al., 2000), although
they do not uniquely express any known marker at this stage. Central cells
move anteriorly as part of the Polonaise movements of the epiblast, long
before primitive streak formation begins
(Foley et al., 2000). The two
cell populations meet and acquire full neural-inducing ability, as well as
organizer markers, by the mid-primitive streak stage (stages 3-3+).
Before this stage, the posterior cells have low neural-inducing ability and
the central cells have none
(Izpisúa-Belmonte et al.,
1993; Tam and Steiner,
1999; Streit et al.,
2000; Robb and Tam,
2004), as assessed by grafts into a remote site of a host embryo.
Recently, a very similar conclusion was reached in Xenopus, based on
the early expression and inducing activity of Chordin
(Kuroda et al., 2004). In this
study, the cells equivalent to the posterior cells were called the blastula
Chordin- and Noggin-expressing cells (BCNE) (although it should be pointed out
that in the chick Noggin is not expressed at all until after the end of
gastrulation, stage 4+).
Together, these observations suggest that the earliest signals for neural
induction originate in part from the hypoblast (visceral endoderm in the
mouse) (Thomas and Beddington,
1996; Belo et al.,
1997; Varlet et al.,
1997; Beddington and
Robertson, 1999), and partly from organizer precursor cells.
However, by the end of gastrulation, most regions of the prospective neural
plate have never been close to the organizer (Hensen's node, embryonic shield
or dorsal lip). This is particularly true for the anterior nervous system
(prospective forebrain) in the chick and mouse, and for the posterior nervous
system in zebrafish and perhaps frog
(Agathon et al., 2003;
Kudoh et al., 2004;
Wilson and Houart, 2004). In
amniotes, node derivatives (prechordal mesendoderm and head process) migrate
anteriorly from the node to underlie the midline of the anterior neural plate,
but are still far from the lateral regions. Some of these node derivatives
have some, but reduced, neural-inducing ability when compared with the
earlier-stage node from which they arose
(Storey et al., 1995;
Foley et al., 1997;
Rowan et al., 1999). The
definitive endoderm, which is also derived from the node, has been suggested
to be an important source of signals for the forebrain
(Knoetgen et al., 1999a;
Knoetgen et al., 1999b;
Withington et al., 2001;
Hallonet et al., 2002;
Chapman et al., 2003). Given
that neither the hypoblast nor node precursor cells can induce the definitive
neural marker Sox2, it remains unknown which tissues are responsible
for emitting the signals that reinforce or complete the neural induction
process and cause Erni- and Sox3-expressing cells to become
neural and acquire Sox2 expression.
How many organizers?
The above discussion raises the issue of whether the embryo possesses more
than one organizer. Certainly, no part of the embryo other than the
gastrula-stage node in amniotes, the dorsal lip in amphibians or the shield in
teleosts can induce a complete ectopic nervous system without also inducing
mesoderm that includes an organizer. However, Otto Mangold
(Mangold, 1933) proposed that
separate inducing activities may exist for the head, trunk and tail regions of
the axis, which reside in different tissues (or at least within the organizer
and its derivatives at different times). The idea of multiple organizers, each
inducing one part of the axis, still has some followers (reviewed by
Stern, 2001;
Niehrs, 2004), and recent
findings in zebrafish suggest that the shield and the more ventral marginal
region emit different signals responsible for inducing the nervous system in
the head and in the trunk/tail (Agathon et
al., 2003; Furthauer et al.,
2004; Kudoh et al.,
2004; Rentzsch et al.,
2004). In the mouse, the anterior visceral endoderm (AVE) is
required for head development, but not for the formation of the more-posterior
CNS, and some have suggested that it might correspond to Mangold's `head
organizer', perhaps through its secretion of BMP and Wnt antagonists
(Bouwmeester et al., 1996;
Belo et al., 1997;
Glinka et al., 1997;
Glinka et al., 1998;
Knoetgen et al., 1999b;
Kazanskaya et al., 2000).
However, it has now been shown that despite being required for head
development, the AVE does not possess neural-inducing activity unless combined
with `early gastrula organizer' (prospective organizer) and the appropriate
responding tissue (future forebrain) (Tam
and Steiner, 1999; Robb and
Tam, 2004). This suggests that the AVE plays only a permissive or
indirect role in neural induction. These results are consistent with findings
in chick and mouse, which implicate the hypoblast/AVE in the positioning of
the primitive streak, in directing its elongation and in the transient
induction of early, but not definitive, neural markers
(Foley et al., 2000;
Streit et al., 2000;
Bertocchini and Stern, 2002;
Perea-Gómez et al.,
2002).
One of the arguments that led to the idea that the mouse AVE might be an
independent `head organizer' came from findings that mouse mutants lacking a
node and its derivatives (for example, HNF3ß mutants)
(Ang and Rossant, 1994;
Weinstein et al., 1994;
Dufort et al., 1998) still
have a fairly complete nervous system. It was also suggested that the
mammalian node cannot induce a forebrain, while the chick node can
(Knoetgen et al., 1999b),
although it now appears that the difference was due to experimental design;
the node of rabbit and mouse embryos can induce forebrain markers just like
the chick node (Foley et al.,
2000; Knoetgen et al.,
2000). Likewise, ablation and exogastrula experiments in other
species have suggested that the Spemann organizer is not required for nervous
system development. As discussed above, tissues other than the shield/dorsal
lip/node do emit signals that can induce the expression of some neural
markers, but no single tissue other than the classical organizer can induce
them all. Despite this, it is also clear that there are regions of the nervous
system that are never close to the organizer (see above); combinations of
signals emanating from different tissues at different times might account for
these tissues acquiring a neural fate.
At present, therefore, there is no conclusive evidence that separate
organizers exist for different parts of the axis, and published results are at
least equally supportive of the alternative `activation/transformation' model
of Nieukwoop (Nieuwkoop et al.,
1952; Nieuwkoop and
Nigtevecht, 1954). This model proposes that the nervous system
that is initially induced is of `anterior' (forebrain) character, and that
later signals `transform' parts of it to more caudal fates.
Neural induction: a decision between epidermis and neural plate?
The default model proposes that high BMP activity defines epidermis, while
absence of BMP specifies neural plate. It has also been proposed that
intermediate concentrations specify the border of the neural plate, including
the region fated to give rise to placodes and neural crest
(Wilson et al., 1997;
Marchant et al., 1998;
Nguyen et al., 1998;
Barth et al., 1999;
Dale and Wardle, 1999;
Nguyen et al., 2000;
Tribulo et al., 2003;
Glavic et al., 2004). However,
at the end of gastrulation in the chick BMP4 and BMP7 are
most highly expressed at the border of the neural plate, as are the BMP target
genes MSX1 and DLX5
(Streit and Stern, 1999b;
Streit, 2002). Indeed, the
border of the chick neural plate is the only region that is sensitive to the
application of BMP protein or BMP antagonists (Chordin and Noggin): BMP causes
the inwards displacement of the border (narrowing the neural plate), while
antagonists cause the reverse (Streit and
Stern, 1999b). Likewise, it has recently been shown that the
misexpression of BMP antagonists in Xenopus only enlarges the neural
plate when injected into blastomeres, the progeny of which include the border
of the neural plate; in a blastomere that does not consistently give rise to
neural crest or placodes, BMP antagonists do not induce ectopic neural markers
(Linker and Stern, 2004;
Delaune et al., 2005). These
findings suggest that BMP activity is crucial in positioning the border
between neural plate and epidermis, defining the territory from which neural
crest and placodes will arise (reviewed by
Streit, 2004).
Indeed, neural induction has always been viewed primarily as a decision
between epidermal and neural fates, particularly because in the Spemann and
Mangold (Spemann and Mangold,
1924) transplants, the fate of the ventral (belly) epidermis is
transformed to a neural fate under the influence of the organizer. A recent
study, however, emphasized that defining the neural plate during normal
development also requires establishing a boundary between the region of the
ectoderm destined to ingress into mesendoderm during gastrulation and the
medial edge of the neural plate (Sheng et
al., 2003). The epiblast gives rise to all three germ layers of
the embryo - at the midline, cells ingress through the primitive streak (in
amniotes) or through the blastopore to give rise to mesendoderm. At the end of
gastrulation, ingression stops and the epiblast that remains adjacent to the
streak is destined to form the medial (future ventral) part of the neural
plate. The zinc-finger transcriptional activator Churchill, isolated in the
early response screen described above, starts to be expressed in the future
neural plate domain of the chick epiblast at around the end of gastrulation
(stage 4). One of its direct targets is the transcription factor SIP1
(Verschueren et al., 1999;
Papin et al., 2002;
Postigo, 2003;
Postigo et al., 2003), which
is expressed in the same domain (not only in chick but also in
Xenopus, fish and mouse). Through Sip1, churchill
downregulates the expression of brachyury, which is essential for
cell ingression through the primitive streak
(Sheng et al., 2003). Sip1
gained its name (Smad-interacting protein 1) because of its ability to bind to
phospho-Smad1, a BMP effector. Given that it takes 4-5 hours for FGF to induce
Churchill, followed by the activation of Sip1 by Churchill,
this might explain why epiblast cells need to receive signals from the
organizer (or FGF signals) for 5 hours before they can respond to BMP
antagonists (Streit et al.,
1998; Sheng et al.,
2003) (see above). These results emphasize the critical importance
of the precise timing and spatial distribution of (1) the signals that
regulate key genes and (2) the pattern of expression of these genes for
gastrulation and neural induction (Fig.
5). As only a handful of secreted signals seem to be important for
controlling multiple events during early development (each of them with
diverse and sometimes opposing roles), the timing of these signals and the
state of the responding cells (that is, their competence) are of crucial
importance.
|
; Lamb et al.,
1993). For these reasons, it has been proposed
(Streit and Stern, 1999b)
that the earliest events in neural induction are equivalent to the induction
of a `pre-border' state, within which cells still retain the ability to give
rise to neural, epidermal, neural crest or placodal fates. Transcriptional networks
In chick, the expression of the transcription factor SOX2 begins
at the end of gastrulation. It is expressed throughout the neural plate. To
date, neither single factors (including FGFs, BMPs, Wnts or their antagonists)
nor any combinations of these, whether applied simultaneously or sequentially,
has been able to induce the ectopic expression of Sox2 directly in
cells that normally do not express this gene
(Linker and Stern, 2004). By
contrast, early `pre-neural' markers such as SOX3, ERNI and
churchill are induced by FGF alone, which is required both for the
expression of these early genes and for the later responses, including
SOX2 expression (Table
2). Perhaps our best chance of identifying the missing signals
will come from analysing the regulatory elements controlling SOX2
expression. An impressive analysis of the chick SOX2 promoter by
Hisato Kondoh's group (Uchikawa et al.,
2003; Uchikawa et al.,
2004) has revealed two crucial elements that together account for
the early expression pattern of SOX2. One of them, N2, drives
expression in the prospective anterior neural plate (the largest part of the
neural plate at stage 4-5); the other, N1, is responsible for the more
posterior expression that elongates caudally as the node regresses and the
spinal cord is laid down (Henrique et al.,
1997; Storey et al.,
1998; Brown and Storey,
2000). Both are conserved between chick and mammals (human, mouse
and rat), and each is extremely complex: N1 contains conserved putative
binding sites for at least 12 known transcription factors, whereas N2 contains
more than 39. Important clues must be embedded in these complex enhancers, the
detailed analysis of which will undoubtedly yield interesting answers to some
of the unanswered questions.
| Box 1. Differences between species or between approaches?
Are there real differences in the mechanisms of neural induction between
species, or are these a consequence of the experimental approaches that can be
used in each? As cross-species organizer grafts always lead to neural
induction, I believe that the key mechanisms will turn out to be conserved.
Xenopus benefits from the ease with which molecules can be
misexpressed or downregulated with a morpholino, which can be injected into a
blastomere up to the 32-cell stage. This approach led to the rapid
identification of BMP signalling as a key player in neural induction. However,
this technique does not allow one to restrict the gain or loss of gene
function to a particular cell group at a particular stage, which is a problem
when the molecules of interest have multiple sequential roles (as do BMPs,
FGFs and Wnts). The introduction of focal electroporation in the chick
(Nakamura et al., 2004
|
What is the role of BMP inhibition in neural development?
From the above evidence, there is no question that the modulation of BMP
activity (including the control of Smad1 phosphorylation at its linker and
C-terminal regions) is crucially important for neural development to occur
normally (see Khokha et al.,
2005). However, I propose that in order to understand neural
induction, we need first to acknowledge the multiple roles of this important
signalling pathway and to design experiments that can distinguish between
them. BMP signalling apparently needs to be inhibited at least three times
during early development to generate a normal neural plate. First, at very
early stages of development (at the blastula stage or even earlier), nuclear
ß-catenin at the dorsal side of the embryo (in amniotes, this may involve
Wnt ligands) regulates BMP expression so that BMP transcription is repressed
dorsally. This repression establishes the initial dorsoventral polarity of the
embryo and contributes to the positioning of the organizer, and perhaps also
to establish differential competence of different ectodermal regions to
respond to later signals. Chordin is probably the most important BMP
antagonist for this step. Second, at the mid-/late-gastrula stage, BMP levels
need to be regulated near the border of the neural plate, to fine-tune the
position and perhaps width of the neural/non-neural border. Here, both BMP and
BMP antagonists have an effect even in amniotes, suggesting that an
intermediate concentration of BMP is required. This process is probably
coordinated with the dorsoventral patterning of the underlying mesoderm, and
is likely to involve Noggin. Third, at the late gastrula/early neurula stage,
BMP needs to be kept downregulated within the neural plate proper to allow for
the continued expression of Sox2 in this domain. There are no
secreted BMP antagonists expressed appropriately for this step, but it is
likely that intracellular factors (such as Sox2 itself and Dach1)
(Kida et al., 2004) play an
important role in this maintenance step.
These three roles of BMP signalling will all be affected in experiments in
which factors that ultimately activate or repress the BMP pathway are
misexpressed or downregulated by injection of morpholinos (e.g.
Khokha et al., 2005) during
very early (pre-gastrula) development. As such, their interpretation should
depend both on the markers being assessed and on the timing of the analysis.
To examine each of these steps independently, both the location and the timing
of gene misexpression needs to be controlled. Acknowledging that neural
induction consists of several steps, and that BMP and other signalling
pathways need to be modulated appropriately in each step, should help to
reconcile results from the different experimental systems and approaches (see
Box 1) used to study neural
induction.
Conclusions
We are only now beginning to understand the true complexity of neural induction. The emerging view is of a cascade of sequential events and of cooperation between different signalling pathways, which together allow cells to make not one, but several, decisions. It has become apparent that concentrating on the signalling molecules alone, without considering the intricacies of the embryological processes they control, can lead to models that are too simplistic to account for the complexity that the embryo must generate during development.
There has been much recent interest in the possibility of causing cultured
stem cells (whether adult or embryonic) to acquire neural fates, with the aim
of producing certain neuronal subtypes, such as dopaminergic neurons, that can
be used to treat neurodegenerative disease. The conditions required to achieve
this are still being debated (Aubert et
al., 2002; Kawasaki et al.,
2002; Bylund et al.,
2003; Stewart et al.,
2003; Ying et al.,
2003a; Ying et al.,
2003b; Jang et al.,
2004; Zhang et al.,
2004), but it now seems likely that an understanding of normal
neural induction, including the dissection of enhancers responsible for
directing the expression of the key `commitment' genes like Sox2, will be an
invaluable tool towards making real progress in this direction.
ACKNOWLEDGMENTS
I am indebted to Les Dale, Claudia Linker, Roberto Mayor and Andrea Streit for invaluable comments on the manuscript, and to Laurent Kodjabachian and Patrick Lemaire for sharing unpublished information. The research by my group on neural induction is funded by grants from the National Institute of Mental Health (NIMH, USA), the Wellcome Trust and the Medical Research Council.
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