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Understanding the somitogenesis clock: what’s missing?
Olivier Cinquin
Howard Hughes Medical Institute and Department of Biochemistry, University of Wisconsin-Madison
433 Babcock Drive, Madison, WI 53706, USA
Correspondence: [email protected]; FAX: (+1) 608-265-5820
Mechanisms of Development 124(7-8), pp501-517
(2007)
posteriorly. The PSM is thus a dynamic structure that can
for many purposes be considered to be at a steady state
(even if its length and the period of somitogenesis vary
with age, Packard & Jacobson, 1976, Tam, 1981). There is
limited cell migration within the PSM (Stern et al., 1988,
Kulesa & Fraser, 2002), but cells do undergo a relative
movement within the PSM, as PSM anterior and posterior
borders move posteriorly.
The mechanism regulating the timing of new somite
segmentation and somite size has been the object of much
attention. A somitogenesis clock has been identified in
chick, mouse, zebrafish, and frog, which consists of oscillatory gene expression in the PSM. For many of these
clock genes, waves of expression originate at the posterior
end and spread anteriorly (see Figure 1). The period of
oscillatory expression is the same as the period of somitogenesis, and a new somite is formed when a wave of
expression reaches the anterior end of the PSM.
Two major questions are how somitogenesis clock oscillations are generated, and how they regulate segmentation. Oscillating genes have mainly been found to belong
to the Notch and Wnt signaling pathways, and more recently also the FGF pathway (Dequ´eant et al., 2006). The
Notch pathway has been proposed to generate oscillations
by forming a negative feedback loop with its modulator
Lunatic fringe, but a positive feedback loop is another
possibility (section 2.1). Her/Hes genes, which are downstream targets of Notch signaling, have also been proposed to generate oscillations by forming a simple negative feedback loop (section 2.2). The Wnt pathway, also
potentially generating the oscillations (section 2.3), offers
numerous possibilities for crosstalk between the signaling pathways active in the PSM (section 2.4). A question
closely related to the generation of oscillations is how oscillations are coordinated between cells (section 2.5).
According to the ‘clock and wavefront’ model, first
proposed by Cooke & Zeeman (1976), segmentation is
regulated by the interaction of a clock and of a wavefront of cell maturity, with the clock determining the time
of segmentation and the wavefront determining the spatial extent of the somite. Molecular identities of suitable
clock and wavefront became known only after the model
was formulated: the clock is that described above, and a
Abstract
The segmentation of vertebrate embryos depends on a
complex genetic network that generates highly dynamic
gene expression. Many of the elements of the network
have been identified, but their interaction and their influence on segmentation remain poorly understood. A few
mathematical models have been proposed to explain the
dynamics of subsets of the network, but the mechanistic
bases remain controversial. This review focuses on outstanding problems with the generation of somitogenesis
clock oscillations, and the ways they could regulate segmentation. Proposals that oscillations are generated by
a negative feedback loop formed by Lunatic fringe and
Notch signaling are weighed against a model based on
positive feedback, and the experimental basis for models of simple negative feedback involving Her/Hes genes
or Wnt targets is evaluated. Differences are then made
explicit between the many ‘clock and wavefront’ model
variants that have been proposed to explain how the clock
regulates segmentation. An understanding of the somitogenesis clock will require addressing experimentally the
many questions that arise from the study of simple models.
Keywords: somitogenesis clock; mathematical models;
notch; lunatic fringe; her1; her7; her13.2; hes1; hes7; wnt;
fgf; retinoic acid; clock and wavefront
1
Introduction
Somitogenesis is the process by which vertebrate and
cephalochordate embryos acquire a segmented structure
(Saga & Takeda, 2001). Somites form by budding off
from the anterior end of the presomitic mesoderm (PSM),
at regular intervals of about 2 hours in mouse, 90 minutes
in chick, and 30 minutes in zebrafish. Although it loses
cells anteriorly to somite formation, the PSM is replenished both by cell proliferation and ingression and grows
1
possible wavefront depends on a gradient of FGF8 signaling within the PSM (Dubrulle et al., 2001, Sawada et al.,
2001). There are many variants of the clock and wavefront model that it is important to distinguish (section 3).
The wavefront corresponds to a boundary between anterior and posterior PSM, which can be defined in terms
of the time segmentation is determined (section 3.1) and
in terms of gene expression (section 3.2); the speed of
wavefront progression is thought to determine somite size
(section 3.3). Finally, some very intriguing phenomena
remain unexplained (section 3.4).
2
Mechanism of the clock
Three main mechanisms have been proposed for the generation of somitogenesis clock oscillations: modulation
of Notch signaling by Lunatic fringe, Her/Hes autorepression, and negative feedback of Axin2 on the Wnt
pathway. The proposed wiring of the zebrafish, chick and
mouse clocks is summarized in Figure 21 , and the mechanisms are reviewed in detail below.
The three main proposed ‘modules’ are theoretically
capable of driving oscillations on their own. They can
be studied independently by making use of the relevant
mutants or morpholino knockdowns, and they have been
mainly considered independently. They have however
been shown to interact in the mouse clock, and understanding this interaction will require more than knowledge
of the mechanism of the individual parts.
It is not known, in any species, which set of genes
‘drives’ the oscillations, i.e. which set of genes must have
oscillatory expression (in a wild-type background or in a
mutant background in which expression of a set of other
clock genes is forced to be constant) for other oscillatory
genes to be expressed normally. Expression of some nonoscillatory genes is required for clock oscillations; these
genes have a role that could be described as ‘permissive’
for the oscillations. It is all but impossible with present
experimental techniques to determine which oscillating
genes are driving the oscillations rather than permitting
them. This is because it is relatively easy to knock out
a gene or misexpress it, but not to enforce expression at
any arbitrary level chosen by the experimenter; it is therefore impossible, for an oscillatory gene whose knocking
out disrupts the clock, to test whether there is a level of
constant expression of that gene that would allow the rest
of the clock to continue oscillating normally.
Figure 1: Schematic representation of the PSM, and of
clock and wavefront models based on boundary specification (A) and on whole somite specification (B). Manipulation of the wavefront by grafted beads coated with
FGF8 disrupts somite size regulation for both models (C).
In the original clock and wavefront model (Cooke & Zeeman, 1976), wavefront progression was controlled by the
clock (D). Color coding represents cell maturity (with
posterior, blue cells being the least mature), and crosshatching expression of a clock gene such as c-hairy1 (ex1 A proposed frog clock is not shown because, even though genes
pression sweeps through the whole PSM during one clock
with dynamic expression have been identified (Jen et al., 1997, 1999,
cycle, three snapshots of which are shown; see section 3.2 Li et al., 2003), less seems to be known about the generation of the
for expression of other PSM genes). In (A) and (B), a oscillations.
new prospective somite or prospective boundary are defined periodically by the represented clock gene interacting with a ‘determination front’. Actual somite segmenta- 2
tion occurs a few cycles after specification (the four specified but yet-unsegmented somites depicted here correspond to the situation in chick). Note that the prospective
boundaries do not define compartments, as cells can cross
from one to the other (Stern et al., 1988, Kulesa & Fraser,
2002).
A Zebrafish clock
B Chick clock
Notch
Notch+
DeltaC
DeltaC
Delta
Lunatic fringe
Notch
Notch+
NICD
her
NICD
deltaC
Her
Delta
hes
Hes
lunatic fringe
C Mouse clock
Notch
Notch+
Lunatic fringe
Dll1
Notch+
NICD
Dll1
Hes
Lunatic fringe
Hes
Dll1
Axin2
Axin2
Wnt signaling
Figure 2: Simplified networks that have been proposed to drive the oscillation in zebrafish (A), chick (B), and mouse
(C) clocks. Zebrafish her1 and her7 genes are summarized as her; see Cinquin (2007) for a more detailed diagram.
Chick and mouse hairy, hey, and hes genes are summarized as hes. NICD: Notch Intra-Cellular Domain. See main
text for the detail of the mechanisms.
2.1
Notch - Lunatic fringe: positive or neg- is a gene that is cyclically expressed in chick and mouse
PSM (McGrew et al., 1998, Forsberg et al., 1998, Aulehla
ative feedback?
& Johnson, 1999)2 , and whose promoter is directly upregulated by Notch signaling (Cole et al., 2002, Morales
The Notch receptor is activated when its extracellular doet al., 2002)3 . Lunatic fringe modifies the Notch receptor
main binds one of the Notch ligands. In the canonical
pathway, proteolysis then releases the intracellular do2 Although a zebrafish homologue is also expressed in PSM, it has
main from the membrane, activating downstream signala very different pattern suggesting that it does not have a role in the
ing. Direct visualization of the cleaved receptor reveals generation of the clock oscillations (Prince et al., 2001).
3 The Notch cofactor CBF-1 can repress Notch targets in the absence
that Notch signaling occurs cyclically in the PSM (Huppert et al., 2005, Morimoto et al., 2005). Lunatic fringe of Notch signaling (reviewed by Bray & Furriols, 2001); repression of
3
post-translationally, making it more sensitive to activation
by its ligand Delta (Panin et al., 1997), and can also act on
the Notch ligands (Panin et al., 2002). Disruption of Lunatic fringe expression disrupts that of other clock components (some stop oscillating, Dale et al., 2003, Serth
et al., 2003, while Axin2 oscillates with an abnormal pattern, Aulehla et al., 2003).
Both negative and positive feedback loops can drive
oscillations (see for example Goldbeter, 2002, for a review). Both types of feedback loops have been proposed
to explain how the interaction between Notch and Lunatic
fringe could drive the somitogenesis clock. In the negative feedback model, Lunatic fringe modifies Notch to
make it less sensitive to activation by Delta. Oscillations
would be generated by alternation between activation of
Lunatic fringe expression by Notch signaling, and repression of Notch signaling by Lunatic fringe (Dale et al.,
2003). Oscillations could also arise from a positive feedback loop between Notch signaling and Lunatic fringe,
with Notch signaling driving Lunatic fringe transcription,
and Lunatic fringe in turn modifying Notch to enhance
its signaling activity (Cinquin, 2003)4 . These latter oscillations are based on ‘substrate depletion’ (Tyson et al.,
2003). Lunatic fringe and modified Notch build up until
they reach a point where the oscillator ‘fires’ and most of
the Notch receptor has been modified by Lunatic fringe.
The reaction then dies off because of the lack of unmodified Notch for Lunatic fringe to act on, and rapid decay of
the modified receptor, which in turn causes Lunatic fringe
transcription to shut off, and the oscillator to return to its
original state.
Manipulation of Lunatic fringe expression has been
used to investigate regulatory interactions. Misexpression of Lunatic fringe results in downregulation of endogenous Lunatic fringe expression, with loss of oscillations or oscillations of reduced amplitude (Dale et al.,
2003, Serth et al., 2003). It has more recently been observed that Notch signaling becomes constantly active in
Lunatic fringe mutants (Morimoto et al., 2005). The negative feedback model can account for these data: misexpression of Lunatic fringe would reduce Notch signalling
and thus transcription of endogenous Lunatic fringe. Loss
of Lunatic fringe would lead to the loss of cyclic repression of Notch signaling. However, the positive feedback
model can also explain the experimental phenotypes. Indeed, depending on the level of Lunatic fringe misexpression, the model predicts either damped oscillations of en-
dogenous Lunatic fringe expression or oscillation arrest
and expression of the endogenous gene at a low baseline. This is exactly what is observed experimentally, with
oscillation arrest in chick (with a misexpression system
that is geared toward high levels of misexpression, Dale
et al., 2003), and oscillation damping in mouse (with a
misexpression system that is likely providing weaker misexpression, Serth et al., 2003). In the positive feedback
model, this results from Lunatic fringe expression depleting the pool of unsensitized Notch by converting it to the
sensitized form, leading to an overall depletion of Notch
levels because the sensitized form is assumed to have a
shorter half-life than the unsensitized one (because it is
more readily used up for signaling). The level of Notch
signaling is reduced to intermediary levels between climaxes and troughs of its normal oscillatory activity, leading to reduced Lunatic fringe expression. Conversely,
knocking out Lunatic fringe in the model positive feedback oscillator leads to constant Notch signaling, at a level
intermediary between troughs and peaks of normal signaling (O. Cinquin, unpublished); this seems consistent with
the observations made by Morimoto et al. (2005).
The positive feedback model also accounts for data that
do not fit in the negative feedback model. Knocking in a
lacZ reporter into the Lunatic fringe locus leads to a smear
of expression in the homozygote, at levels which seem to
be lower than peak expression levels in heterozygotes carrying one wild-type copy of Lunatic fringe and one lacZ
knockin copy (Chen et al., 2005).
It has been proposed that interlocked positive and negative feedback loops could contribute to the robustness
of circadian oscillations (Ueda et al., 2001, Cheng et al.,
2001, Hong et al., 2007). It would therefore not be surprising if there were positive feedback circuits in the somitogenesis clock. The circuitry of the circadian clock has
proven to be complex, but most interestingly the first
in vitro reproduction of circadian oscillations has suggested a possible positive feedback mechanism (Nakajima
et al., 2005, Mehra et al., 2006), rather than negative transcriptional feedback as previously thought (Ishiura et al.,
1998). Also, although negative transcriptional feedback
has long been considered the basis for circadian rhythmicity, much evidence is accumulating that questions this
dogma (reviewed by Lakin-Thomas, 2006). It is important to distinguish between positive and negative feedback
in the somitogenesis clock, because the two mechanisms
are expected to impart very different properties to the osLunatic fringe in the absence of Notch signaling or activation in the pres- cillators (for example in terms of responses to perturbaence of signaling are likely to be similar in the way they could generate tions in biochemical rates and delays).
oscillations.
4 Note that this does not contradict the requirement of a negative feedback cycle of length greater than 1 for the existence of oscillations in a
system without delays (Snoussi, 1998), as the ‘biological’ positive feedback described above in fact leads to negative feedback circuits, as defined mathematically by the Jacobian matrix of the set of ordinary differential equations describing the dynamics of the system.
There are many elements in the somitogenesis clock,
and it is possible that Lunatic fringe does not mediate
its effects on the Notch receptor (or its ligands) directly.
It is also a possibility that Lunatic fringe really does inhibit Notch activation by Delta, contrary to what has been
4
observed more directly in other experimental systems.
However, a model with a positive feedback loop between
Notch and Lunatic fringe seems to be the most parsimonious explanation of current experimental data.
Finally, transcription of the Notch ligand Dll1 has recently been observed to be oscillatory in mouse PSM
(Maruhashi et al., 2005), similar to oscillatory transcription of the Notch ligand DeltaC in zebrafish PSM. This
might not provide a mechanism for autonomous oscillations of the Notch pathway, as it is not straightforward
for a simple positive feedback loop to drive oscillations
without substrate depletion, even when delays are taken
into account (Smith, 1987, Smolen et al., 1999). However,
since Dll1 transcription is under control of Wnt signaling
(Hofmann et al., 2004, Galceran et al., 2004), Dll1 could
provide a molecular link between the Wnt and Notch pathways. It is thus possible that oscillatory activation of the
mouse Notch pathway is downstream of Wnt pathway oscillations, as proposed by Aulehla et al. (2003), but the
disruption of Notch oscillations by mutations of members
of the Notch pathway suggests that Notch pathway oscillations are not just a passive response of periodic stimulation by Wnt signaling.
2.2
transcription from its own promoter, in a model system
involving cultured cells (Bessho et al., 2001a, Chen et al.,
2005; it is however a possibility that Hes7 can repress its
own expression in combination with other factors, present
in the PSM but not in cultured cells, or that Hes7 is part
of a negative feedback loop involving other factors). Interestingly however, Hes7 can block Notch-mediated activation of its promoter (Bessho et al., 2003, Chen et al.,
2005). Because Notch activation is cyclic in the PSM and
depends on other factors such as Lunatic fringe, potential self-repression of Hes7 cannot be considered independently of the rest of the clock. Stabilization of Hes7
protein (engineered by a point mutation) leads to a disruption of oscillations, which can be explained within the
framework of a simple self-repression model (Hirata et al.,
2004), provided that strict requirements are met on the
precise mechanism of Hes7 self-repression (Zeiser et al.,
2006). Another possibility is that the average level of
Hes7 repression must be within a certain range to allow
functioning of the clock.
Two zebrafish her genes, her1 and her7, show oscillatory expression in the PSM and are essential for clock
oscillations and normal segmentation (Henry et al., 2002,
Oates & Ho, 2002, Holley et al., 2002). Her1 represses expression of its promoter in a cell-culture assay (Kawamura
et al., 2005), and self-repression of her genes has been
proposed as a basis for the oscillations of the zebrafish
clock (Oates & Ho, 2002, Holley et al., 2002, Lewis,
2003). A problem with that model is that morpholino
blocking of her1 or her7 mRNA translation can lead
to downregulation of their transcription (Gajewski et al.,
2003), while a simple negative feedback loop would predict upregulation of transcription if the repressor protein
cannot be translated. Her1 and Her7 are bHLH proteins,
a family whose members normally function as dimers
(Davis & Turner, 2001), and reproduction of knockdown
phenotypes can be achieved by taking into account the formation of Her dimers that repress transcription with different potencies (Cinquin, 2007).
Her/Hes
A number of Her/Hes genes, which encode transcriptional
repressors of the basic helix-loop-helix (bHLH) family
often downstream of Notch signaling (Iso et al., 2003),
are expressed dynamically in the PSM (Palmeirim et al.,
1997, Jouve et al., 2000, Holley et al., 2000, Oates & Ho,
2002, Leimeister et al., 2000, Bessho et al., 2001b). The
expression of one of these genes, mouse Hes1, oscillates
in cultured cells in response to serum shock (Hirata et al.,
2002, Masamizu et al., 2006; see also William et al., 2007,
for human cells), and it has been proposed that delayed
Hes1 autorepression could be the basis for this oscillation (Jensen et al., 2003, Lewis, 2003, Monk, 2003, Barrio et al., 2006). Since additionally the period of Hes1
oscillations is the same in cultured cells and in mouse
PSM, this raises the possibility that Hes1 self-repression
is also a mechanism for driving the somitogenesis clock.
However, Hes1 mouse knockouts have no somitogenesis
phenotype (Ishibashi et al., 1995, Ohtsuka et al., 1999),
showing that Hes1 autorepression, if it does occur, is not
necessary; Hes1 could be redundant with other factors of
the clock.
Hes7 is a related protein that is essential for mouse
somitogenesis (Bessho et al., 2001b, Hirata et al., 2004),
and it has been proposed that delayed self-repression of
Hes7 is responsible for its oscillatory expression (Hirata
et al., 2004; see also Bessho et al., 2003). The difference
in the phenotypes of Hes1 and Hes7 knockouts could be
due to differences in dimers they form in vivo. Hes7 has
been shown to be unable by itself to significantly repress
In summary, it is possible that Hes autorepression is
part of the ‘core’ mechanism of the mouse somitogenesis clock. Hes7 autorepression has however only been
shown to occur in the presence of Notch signaling, which
is itself cyclic, and it is therefore not possible at present
to assume that Hes7 self-repression is by itself the core
mechanism of the somitogenesis clock. Her autorepression in zebrafish does not carry that complication, at least
in the case of Her1, but it has not been established whether
Notch signaling is necessary for the existence of the oscillations or for intercellular synchronization (Holley et al.,
2000, 2002, Jiang et al., 2000). In vivo imaging of oscillations in Delta mutants (Jiang et al., 2000) could resolve
that latter question.
5
2.3
Wnt signaling
Finally, Dkk1 is a secreted inhibitor of Wnt signaling
(Glinka et al., 1998; reviewed by Niehrs, 2006), whose
expression is induced by Wnt signaling (Niida et al.,
2004, Chamorro et al., 2005). Oscillation of Dkk1 mRNA
could only be detected by the use of an intronic probe
(Dequ´eant et al., 2006), suggesting that even though transcription is rhythmic, stability of the mRNA might prevent
it from undergoing high-amplitude concentration oscillations. Mouse Dkk1 knockouts have segmentation defects
whose causes have not yet been investigated (MacDonald
et al., 2004).
Wnt signaling thus offers a number of simple negative feedback loops, any of which could theoretically
be able to single-handedly drive the somitogenesis clock
(similar negative feedback loops exist for the Notch and
FGF pathways, with oscillation of the inhibitors Nrarp
and Sprouty2, Dequ´eant et al., 2006). However, even
though Wnt signaling is critical for normal functioning
of the clock, only one of the Wnt inhibitors tested so far
(Dkk1) has proven necessary by itself. Negative feedback
is a ubiquitous feature of signaling pathways (Freeman,
2000), and it would probably be undesirable for all feedback inhibitors to cause their signaling pathway to enter an oscillatory state. It is possible that a combination
of Wnt inhibitors acts redundantly to cause Wnt signaling to be oscillatory in the mouse PSM, that some members of the pathway have not been identified, that the
mouse Wnt pathway is in fact unable to generate oscillations in isolation, or that it is able to generate oscillations in isolation by an unknown mechanism that could
be much more sophisticated than a single negative feedback loop. The latter possibility is intriguing given the
great complexity of Wnt signaling. A biochemical study
of Wnt signaling has for example shown that paradoxical effects can occur, with high concentrations of Axin
stabilizing β-catenin rather than promoting its destruction
(Lee et al., 2003). Also, oscillations in the PSM have been
almost exclusively studied at the mRNA level, but Wnt
signaling components such as Axin are heavily regulated
post-translationally (Willert et al., 1999, Yamamoto et al.,
1999). Inhibition of protein synthesis blocks the chick
somitogenesis clock after at most one round of oscillation
(depending on the gene readout; Palmeirim et al., 1997,
McGrew et al., 1998), but this does not exclude a role for
post-translational modifications having a role in the generation or shaping of the oscillations. This is because a
block in protein synthesis could arrest the clock by leading to a depletion of short-lived proteins, rather than by
breaking an essential transcription - translation feedback
loop.
Wnt/β-catenin signaling is cyclic in mouse PSM (Aulehla
et al., 2003), and induces cyclic transcription of the Wnt
signaling inhibitors Axin2 (Aulehla et al., 2003) and Nkd1
(Ishikawa et al., 2004); the Dact1 (Suriben et al., 2006),
and Dkk1 (Dequ´eant et al., 2006) inhibitors also show oscillatory expression. Axin2, Dact1, and Dkk1 phases of
oscillation are closely related, and distinct from the phases
of Notch-related genes and Nkd1. Wnt3a mRNA is expressed in the mouse tailbud and it has been proposed that
Wnt3a protein forms a posterior-anterior gradient in the
PSM, because Axin2 is downstream of Wnt signaling and
oscillates with a higher amplitude in posterior PSM than
in anterior PSM (Aulehla et al., 2003).
Axin2 is related to Axin, a critical component of the
Wnt signaling pathway that acts as a scaffold for the βcatenin destruction complex (Logan & Nusse, 2004). Axin
and Axin2 are functionally equivalent (Chia & Costantini,
2005) but their expression is differentially regulated: Axin
is ubiquitous while Axin2 expression is tissue-specific and
downstream of Wnt signaling (Jho et al., 2002, Leung
et al., 2002). Based on the persistence of some Axin2 oscillation in the Notch pathway mutant Dll1, and on the
disruption of Notch pathway oscillations in the Wnt3a
hypomorphic mutant vestigial tail, Aulehla et al. (2003)
proposed that a Wnt signaling - Axin2 negative feedback
loop is responsible for driving the mouse somitogenesis
clock. Wnt signaling would drive transcription of Axin2
mRNA, and Axin2 protein would inhibit Wnt signaling.
However, Axin2 mutants have no somitogenesis phenotype (Yu et al., 2005), which suggests that either Axin2
does not play a significant role in the generation of the
oscillations, or that it functions in the clock redundantly
with other genes.
Nkd1 inhibits Wnt signaling by binding to the mediator Dishevelled (Rousset et al., 2001, Wharton et al.,
2001), and stands out among oscillatory Wnt signaling
inhibitors in that it oscillates in phase with Notch-related
genes (Ishikawa et al., 2004). Its expression is dependent
on Wnt signaling (as assayed with the vestigial tail hypomorph), but oscillatory expression is disrupted in the
Notch pathway mutant Hes7, suggesting that Wnt oscillations might not be independent of the Notch pathway.
Mouse Nkd1 knockouts have no reported somitogenesis
phenotype (Li et al., 2005), which is not due to redundancy with the similar gene Nkd2 (Zhang et al., 2007).
Dact1, also known as Dpr1/Frd1, also interacts with
Dishevelled (Cheyette et al., 2002) and can promote its
degradation (Zhang et al., 2006), antagonizing Wnt signaling. In different contexts Dact genes can however promote Wnt signaling (Gloy et al., 2002, Waxman et al.,
2.4 Crosstalk
2004), and it has been proposed that members of the Dact
family could regulate expression of Wnt pathway genes in Crosstalk between the pathways involved in the somitoparallel to the canonical pathway (Hikasa & Sokol, 2004). genesis clock has been extensively documented in differ6
Drosophila (Carmena et al., 2006). There are thus numerous ways in which the three signaling pathways known to
be active in the PSM could be linked. It will be essential to
determine exhaustively which molecular interactions actually occur in the PSM, and how they contribute to the
generation or shaping of the clock oscillations.
ent contexts. ERK — downstream of the FGF pathway
in chick, zebrafish, and frog PSM — can phosphorylate
Groucho, a cofactor in the repression of Notch and Wnt
targets in the absence of signaling, and thereby attenuate its activity (Hasson et al., 2005; reviewed by Hasson
& Paroush, 2006 and Sundaram, 2005). ERK also regulates cleavage of the Notch receptor (Kim et al., 2006).
Within the context of the zebrafish clock, FGF drives transcription of her13.2, which in turn influences her autorepression (Kawamura et al., 2005). The kinase Akt, downstream of FGF signaling in mouse (Dubrulle & Pourqui´e,
2004), can influence Wnt signaling in a variety of ways
(Fukumoto et al., 2001, Gherzi et al., 2006, Fang et al.,
2007). Thus, FGF signaling can influence Notch and Wnt
signaling.
Notch signaling can regulate β-catenin activity, through
a non-canonical pathway in conjunction with Axin (Hayward et al., 2005, 2006), or through induction of Hes1
(Deregowski et al., 2006). Notch signaling can induce
expression of MAPK phosphatases (Berset et al., 2001,
Lee et al., 2006, Kondoh et al., 2007), potentially antagonizing FGF signaling. Within the context of the zebrafish
clock, the Notch pathway has been implicated in the maintenance of Cyp26 expression (Echeverri & Oates, 2007),
providing a potential interaction with the FGF pathway
(see section 3.2).
Wnt signaling can impinge on activation of MAPK
(Yun et al., 2005, Park et al., 2006, Jeon et al., 2007).
Dishevelled can also inhibit Notch signaling by physical
interaction with Notch (Axelrod et al., 1996, reviewed by
Blair, 1996, and Ramain et al., 2001). Thus, Wnt signaling can influence FGF and Notch signaling. Within
the context of the mouse clock, Wnt signaling has been
proposed to control expression of FGF8 (Aulehla et al.,
2003), and Wnt pathway manipulation alters Notch pathway activation (Aulehla et al., 2003), although the molecular mechanism is not clear. A possible molecular mechanism involves Snail genes, which are transcriptional repressors5 involved in epithelial to mesenchymal transitions (Barrallo-Gimeno & Nieto, 2005). Snail1 (mouse)
and Snail2 (chick) expression is oscillatory, and depends
on Wnt and FGF signaling (Dale et al., 2006), consistent with dependence of the Snail1 promoter on ERK
and PI3 signaling (Peinado et al., 2003, Barber`a et al.,
2004). Snail2 overexpression represses Lunatic fringe
cell-autonomously (and leads to loss of PSM identity). Interestingly, Snail1 represses its own expression, adding to
the number of negative feedback loops that have been proposed to drive the somitogenesis clock (Peir´o et al., 2006).
Finally, the Ras-binding protein Canoe, also known as
AF6 or Afadin, is expressed in PSM (Ikeda et al., 1999)
and modulates the Notch, Wnt, and Ras pathways in
2.5
Intercellular clock synchronization
Early experiments on the clock showed that oscillatory expression could go on after sectioning of chick and mouse
PSM and separate incubation (Palmeirim et al., 1997, McGrew et al., 1998, Forsberg et al., 1998; this has been confirmed for many genes of the clock, and more recently investigated in detail by cutting chick PSM into more than
two pieces, Maroto et al., 2005). This was first interpreted
as suggesting that the clock was cell-autonomous; there
are however a number of reasons to expect some form of
coupling (Jiang et al., 2000, Cinquin, 2003).
It has recently been shown that dissociation of mouse
PSM cells does not disrupt individual oscillations, but
leads to a loss of synchrony between cells (Masamizu
et al., 2006). This strongly suggests that local coupling keeps cells oscillating in synchrony, which has been
shown directly in zebrafish by the synchronization of
PSM grafts (Horikawa et al., 2006).
The potential mechanism for intercellular synchronization of the zebrafish clock seems reasonably straightforward, as oscillations of the Notch ligand Delta could bring
neighboring cells into synchrony (as shown in silico by
Lewis, 2003 and Cinquin, 2007). This is also a possibility
in the mouse clock, as transcription of the Notch ligand
Dll1 is oscillatory (Maruhashi et al., 2005). In zebrafish,
it has been proposed that DeltaC, whose expression is oscillatory, acts to synchronize adjacent cells while DeltaD,
whose expression is not oscillatory, would prime expression of clock genes in progenitors (Mara et al., 2007).
Another potential mechanism for the mouse and chick
clocks is provided by Lunatic fringe, which potentiates
Notch activation by Delta, has oscillatory expression, and
has been observed to be secreted in some contexts (Wu
et al., 1996, Panin et al., 1997). It has been suggested
that Lunatic fringe only functions intracellularly, based
on genetic analysis of the Drosophila wing disc (Irvine
& Wieschaus, 1994, Kim et al., 1995), on the fact that Lunatic fringe localizes predominantly to the Golgi (Hicks
et al., 2000), as does Drosophila Fringe (Munro & Freeman, 2000), and on the facts that forcibly-secreted Fringe
is less active than wild-type Fringe (Munro & Freeman,
2000) and secreted Fringe does not have detectable activity when applied to cells cultured in vitro (Br¨uckner
et al., 2000). However, predominant localization of Lunatic fringe to the Golgi does not preclude activity at other
5 Note however that Snail2 has been shown to activate its own prosites (perhaps with lower activity), and extracellular activmoter (Sakai et al., 2006).
ity could be context-dependent, especially since the activ7
3
ity of Fringe proteins requires UDP-N-acetylglucosamine
to transfer to acceptor proteins (Moloney et al., 2000).
Medium conditioned by cultured cells secreting Fringe
protein has inductive activities on Xenopus embryos (Wu
et al., 1996), and misexpression in the Drosophila wing
disc of Golgi-tethered Fringe (which is not detectably secreted in cultured cells) and wild-type Fringe does not
have the same effect (compare Figures 2f and 2g of
Br¨uckner et al., 2000).
Secretion and extracellular activity of Lunatic fringe in
chick and mouse PSM thus seems a possibility, which
can lead to local cell synchronization in simulations of
the somitogenesis clock based on the interaction of Lunatic fringe and the Notch receptor (Cinquin, 2003). It
is however also possible that synchronization is mediated
by some other factor, or combination of factors (perhaps
involving Wnt signaling in mouse).
The problem of synchronization is not straightforward
to address experimentally. It seems that at present there is
no method to visualize individual cellular oscillations in
vivo, which would make it possible to study the correlation between the dynamics of expression of neighboring
cells. Visualization of individual, dissociated cells is possible, but the loss of cell-cell contact probably leads to the
loss of intercellular communication, and PSM dissociation probably also alters FGF8 signaling (see for example Kuroda et al., 2005), and therefore possibly also the
clock (see below). PSM grafts, as performed by Horikawa
et al. (2006), could be coupled to real-time in vivo imaging to provide detailed kinetic data that could be used to
test mathematical models.
Clock & wavefront
The clock and wavefront model was proposed by Cooke
& Zeeman (1976), based on experimental data from Xenopus. One of the major goals of the model was to explain
the powerful regulation of somite number: that number
varies very little with changes in embryo size, whether
natural or experimentally-induced (Cooke, 1975); somite
cell number, rather than somite count or cell size, changes
in response to alterations in total body size. In the model,
the progression of a wavefront of cell maturity was supposed to be alternatively inhibited and accelerated by an
oscillator, so that cells destined to segment together would
be reached by the wavefront, and undergo a change in adhesive properties, within a short time-frame. Regulation
of somite size (and therefore somite number) was proposed to depend on an early positional information gradient, formed by the diffusion from a source and the destruction by a sink of a morphogen molecule. The positional
information gradient would set up the original pattern of
cell maturity, and ensure that the PSM contains the same
number of prospective somites, irrespective of its size.
The regulative abilities of PSM have been argued to be
much weaker in species other than Xenopus (Primmett
et al., 1988), and the question of size regulation has not
been addressed after the molecular identities of somitogenesis regulators were established. The clock and wavefront model has however become very popular after the
discovery of candidates for the clock (Palmeirim et al.,
1997) and the wavefront (Sawada et al., 2001, Dubrulle
et al., 2001). It is crucial to note that what is referred to
as the ‘clock and wavefront’ model in the recent literature
is conceptually very different from the original model described by Cooke & Zeeman (1976). Two differences are
that
Spatiotemporal pattern of the clock
The relative timing of cellular oscillators in the PSM is
such that, for many of the oscillatory genes, waves of expression propagate from the posterior end to the anterior
end, shrinking in the process. As noted above, the propagation of these waves is not detectably affected, at least
for a few cycles, by sectioning of the PSM. It is likely
that oscillations are shaped by positional information in
the PSM, the FGF8 gradient being an obvious candidate.
Modulation of the strength of intercellular coupling, by
an unspecified molecular mechanism, can lead to in silico reproduction of the spatiotemporal pattern of the clock
(Cinquin, 2003). More interestingly, a molecular link has
been uncovered in zebrafish between the Notch and FGF
signaling pathways: Her1 autorepression is enhanced by
heterodimerization with Her13.2, whose transcription is
FGF-responsive (Kawamura et al., 2005). In a molecular
model of the zebrafish clock, this link is sufficient to establish the clock spatiotemporal pattern (Cinquin, 2007).
Testing of that model will require further experimental
data on dimerization of Her proteins.
• the original clock and wavefront model supposes
that segmentation happens at the level of the whole
somite, by a change in locomotory and/or adhesive
properties of all cells (Figure 1A), while for other
models (such as that of Dubrulle et al., 2001) it is
the somite boundaries, rather than the somites themselves, that are specified: cells are induced to become
boundary cells if they are reached by the wavefront at
a specific phase of their oscillation (Figure 1B). This
latter model, in which a border is formed prior to
somite compaction, would be compatible with data
from zebrafish mutants that show border specification without somite compaction (Henry et al., 2000).
Experiments in chick suggest however that somite
border formation is induced by the juxtaposition of
Lunatic fringe-expressing and non-expressing cells
(Sato et al., 2002), and would therefore not be directly specified by the clock and wavefront.
• the original clock and wavefront model, contrary to
8
a common assumption, supposes that the wavefront
of maturity is pushed posteriorly by each clock pulse
(Figure 1D); this is somewhat similar to the progressive activation of Hox genes by clock pulses proposed by Z´ak´any et al. (2001). In more recent incarnations of the model (for example that of Dubrulle
et al., 2001) wavefront and oscillator do not influence
each other, and interact only to regulate segmentation: the wavefront is supposed to progress independently of the clock, at constant speed.
wave’ of somite determination, similar to the wavefront of
somite formation but located more caudally. Cells reached
by that wave would be distributed into somites, but that
distribution would only become visible at the actual time
of segmentation (Figure 1A). Heat shocks were proposed
to affect somite delimitation by the ‘prior wave’. Disruption of somitogenesis by heat shocks is a phenomenon
shared (with some differences) across species; the first defects occur after 6 to 7 somites in chick (Stern et al., 1988),
4 to 5 somites in zebrafish (Roy et al., 1999), 4 somites in
rats (Cuff et al., 1993), but less than 2 somites in mouse
(Li & Shiota, 1999).
The existence of a chick ‘determination front’ has
been addressed more directly by Dubrulle et al. (2001),
who inverted the anteroposterior axis of one-somite long
PSM regions. Such inversions disrupt segmentation only
when performed anterior to somite -IV (see Figure 1A
for prospective somite numbering after Pourqui´e & Tam,
2001). Consistent with this, grafting of FGF8 coated
beads can affect segmentation only of cells located posterior to somite -IV (Figure 1C), even though anterior cells
do respond to FGF8 beads, at least in terms of ERK phosphorylation (as shown in Figure 1 of Delfini et al., 2005).
A similar zebrafish determination front has been proposed
by Sawada et al. (2001), who observed normal segmentation of 4 to 5 somites in zebrafish after soaking embryos
in an FGF8 inhibitor.
It follows from the data in the previous paragraphs that
if an FGF8 wavefront is to specify chick somite boundaries in conjunction with the clock, that specification must
occur around somite -IV (in chick), and that is where the
wavefront relevant to segmentation models must be. This
is consistent with the concentration of FGF8 (at least at
the mRNA level) varying quickly in that region, compared
to other places in the PSM (Figure 1E-H of Dubrulle et al.,
2001): for specification to occur precisely and to lead
to reproducible somite lengths, the FGF8 concentration
should show a sufficiently steep gradient. Downregulation
of FGF and Wnt receptors has been found to be necessary
in frog for correct positioning of the wavefront (Nagano
et al., 2006), which is interesting given that receptors can
interfere with morphogen gradient formation (Kerszberg
& Wolpert, 1998; see Lander, 2007, for a review).
Local manipulation of FGF8 signaling does affect the
spatiotemporal pattern of clock gene expression (Sawada
et al., 2001, Dubrulle et al., 2001), which shows that
clock and wavefront are not independent. Retinoic acid
signalling, thought to oppose FGF8 signaling, has been
shown to have a role in the setup or maintenance of oscillation synchrony between the left and right sides of
the PSM (Vermot & Pourqui´e, 2005, Vermot et al., 2005,
Kawakami et al., 2005). Even stronger evidence for FGF
signaling acting on the clock is the direct molecular link
identified in zebrafish (Kawamura et al., 2005).
Importantly, shaping of clock gene expression by FGF8
signaling does not mean global inhibition of FGF signaling should result in short-term disruption of clock oscillations. This is because if changes in levels of FGF8 signaling result in phase-shifting of the clock (as observed
in silico by Cinquin, 2007), uniform inhibition of FGF8
signaling in the whole PSM could merely block phaseshifting or cause global phase shifting, resulting in a spatiotemporal pattern that is grossly similar, at least for a
few cycles, to a wild-type pattern.
A complication about the wavefront is that transcription of elements of the FGF8 signaling pathway has been
reported to oscillate in the posterior PSM in phase with
that of Notch targets, blurring the distinction between
clock and wavefront (Dequ´eant et al., 2006; oscillations
of ERK phosphorylation have however not been reported
by Sawada et al., 2001, or Delfini et al., 2005). This does
not seem to preclude the FGF8 pathway from playing its
role in the ‘clock and wavefront’ models, if for example
its activity needs to drop over a period of time greater than
the oscillation period for PSM cells to switch from posterior to anterior identities.
3.1
3.2
Determination front
It was first observed in Xenopus and Rana that heat shocks
disrupt somitogenesis, but only after a few normal somites
have formed (Elsdale et al., 1976, Pearson & Elsdale,
1979). In Rana, around 3 to 4 normal somites are formed
before the onset of the perturbations (the number is 5 in
Xenopus); importantly, that number varies little with the
somitogenesis stage at which the heat shock is applied.
This led the authors to propose the existence of a ‘prior
Spatially-regulated expression in the
PSM
Anterior and posterior PSM can be distinguished by differential gene expression. Posterior PSM expresses pMesogenin1 (mouse, with an anterior border around somite
-II; Yoon et al., 2000), also known as Mespo (frog, with
an anterior border around somite -III, Joseph & Cassetta,
1999; zebrafish, Yoo et al., 2003) and cMespo (chick, with
an anterior border around somite -III, Buchberger et al.,
9
2000). The domain of pMesogenin1 expression abuts that
of Paraxis (Yoon et al., 2000), a bHLH gene required
for somite epithelialization (Burgess et al., 1996) and expressed in anterior PSM (Burgess et al., 1995).
Anterior PSM expresses pairs of homologous bHLH
genes whose expression patterns closely overlap: Mesp1
and Mesp2 (1 stripe in mouse, Saga et al., 1997, Takahashi
et al., 2007), also known as Thylacine1 and Thylacine2
(2 stripes in frog, Sparrow et al., 1998), c-meso1 and cmeso2 (1 to 2 stripes in chick, Buchberger et al., 1998),
mesp-a and mesp-b (1 to 3 stripes in zebrafish, Sawada
et al., 2000).
The border between anterior and posterior PSM, as defined by the genetic expression just described, apparently
correlates with the determination front mentioned above:
the segmentation of anterior cells seems to be determined,
and unaffected by heat shocks. In zebrafish, the T-box
transcription factor fss/tbx24 has a role in mediating the
transition between posterior and anterior PSM (Holley
et al., 2000, 2002, Nikaido et al., 2002).
et al., 2000) and in PSM (Diez del Corral et al., 2003).
Chick PSM contains high levels of retinoic acid during
early somitogenesis; retinoic acid is subsequently downregulated in posterior PSM (Maden et al., 1998). The situation in mouse is comparable, with retinoic acid signaling
activity first present in anterior PSM, but retracting further anteriorly after the first 10 somites are formed (Sirbu
& Duester, 2006). Retinoic acid can be synthesized from
retinaldehyde (itself derived from vitamin A) by any of
a handful of enzymes (Duester et al., 2003, Lin et al.,
2003, Chambers et al., 2007). Retinoic acid in the PSM is
thought to be produced by RALDH2, which is expressed
in PSM and somites and follows a similar anterior retraction during early somitogenesis as observed for retinoic
acid signaling activity (Sirbu & Duester, 2006, Swindell
et al., 1999, Xavier-Neto et al., 2000, Chen et al., 2001,
Grandel et al., 2002, Blentic et al., 2003). Cyp26 degrades retinoic acid and is expressed in posterior PSM in
chick during early somitogenesis (Swindell et al., 1999,
Blentic et al., 2003), in mouse (Fujii et al., 1997), in zebrafish (Dobbs-McAuliffe et al., 2004), and in frog (de
Roos et al., 1999). Expression of the retinoic acid synControl of the wavefront
thesizing and degrading enzymes in distinct domains —
Reduced FGF8 signaling is thought to be the crucial cue source and sink — has been proposed as a mechanism
causing the transition from posterior identity to anterior to establish a morphogen gradient, in a different context
identity. FGF8 mRNA is expressed in a gradient in the (Maden, 1999, Swindell et al., 1999).
PSM, with strong posterior expression (Sawada et al.,
Treatment of chick PSM explants with retinoic acid
2001, Dubrulle et al., 2001). Grafting of FGF8 beads, downregulates FGF8 (Diez del Corral et al., 2003); in
or misexpressing FGF8 throughout the PSM, enforces a frog, treatment with retinoic acid actually induces FGF8,
posterior identity (Dubrulle et al., 2001). Dubrulle & but also induces MKP3 — an inhibitor of FGF sigPourqui´e (2004) showed that FGF8 mRNA is transcribed naling — and does expand PSM of anterior character
in PSM progenitors but not in the PSM itself, and pro- at the expense of posterior PSM (Moreno & Kintner,
posed that decay of the mRNA underlies the gradient: be- 2004). Ectopic retinoic acid signaling in the posterior
cause there is a loose correlation between the anteropos- PSM of mouse Cyp26 knockouts downregulates the posterior position of a cell within the PSM and the time it terior markers FGF8 and Wnt3a (Sakai et al., 2001, Abuhas been in the PSM, a longer time has elapsed since the Abed et al., 2003). Conversely, disruption of retinoic acid
stop of FGF8 mRNA transcription in anterior cells than in synthesis by targeting of Raldh2 expression, by incubaposterior cells, and anterior cells therefore have a smaller tion with chemical inhibitors, or by vitamin A deprivation,
remaining pool of FGF8.
results in upregulation of FGF8 in mouse (Molotkova
Interestingly however, neither a zebrafish FGF8 mutant et al., 2005, Vermot et al., 2005), chick (Diez del Cornor a mouse conditional knockout that loses FGF8 expres- ral et al., 2003, Vermot & Pourqui´e, 2005) and zebrafish
sion in the PSM show a somitogenesis phenotype (Reifers (Kawakami et al., 2005). Retinoic acid signaling is thus
et al., 1998, Perantoni et al., 2005). Potential explanations likely to repress FGF8 signaling.
for the lack of a phenotype include ligand redundancy,
Ectopic FGF8 signaling, or mimicking constitutivelydiffusion of FGF8 from other sources in the embryo, or
active
FGF signaling, prevents expression of Raldh2
perhaps redundancy with Wnt signaling. Wnt signaling
(Diez
del
Corral et al., 2003, Delfini et al., 2005). FGF8
has been proposed to control the FGF8 gradient in mouse
signaling
is
thus likely to repress retinoic acid signaling.
(Aulehla et al., 2003), but experiments in frog suggest that
Sirbu & Duester (2006) have recently brought crucial
Wnt signaling might be able to act in parallel to FGF to
precisions to the model of antagonism between FGF8 and
position the wavefront (Nagano et al., 2006).
retinoic acid. Firstly, retinoic acid signaling is only necessary for normal somitogenesis during early stages; thus,
Antagonism between FGF8 and retinoic acid
even though experimental manipulation of the retinoic
FGF8 signaling has been proposed to act in opposition acid pathway affects FGF8 expression, such regulation
with retinoic acid signaling in the limb bud (Mercader seems to happen in vivo only at a specific stage. This
10
tation mechanism of early somites that makes them more
resilient to clock perturbations (J¨ulich et al., 2005), and to
the segregation of PSM progenitors depending on the time
at which they contribute to the PSM (Szeto & Kimelman,
2006; reviewed by Holley, 2006).
is compatible with normal segmentation of posterior PSM
that has been physically separated from anterior PSM and
should therefore not have any anterior source of retinoic
acid (Packard, 1978). Secondly, endogenous retinoic acid
acts to limit FGF8 expression in the ectoderm that overlies the PSM, rather than in the PSM itself (the PSM was
proposed to be less sensitive to retinoic acid because of the
expression of COUP-TFII, which antagonizes the action
of retinoic acid receptors). This suggests that diffusion
of FGF8 from the ectoderm might impact the PSM. Finally, it is noteworthy that mouse reporters suggest that
retinoic signaling is not graded along the PSM; rather,
there is a sharp boundary of signaling in anterior PSM
(Vermot et al., 2005). This sharp boundary could be due
to the ability of retinoic acid receptors to provide sharp
thresholds in their transcriptional readout of retinoic acid
concentrations (Kerszberg, 1996).
3.3
3.4
A particularly intriguing feature of PSM cell response to
FGF8 signaling is that cells located anterior to a grafted
FGF8 coated bead respond much more strongly than cells
situated caudal to the bead, at the same distance (Delfini
et al., 2005). This complicates the interpretation of bead
grafting experiments, and could be related to the asymmetrical effect on segmentation of FGF8 beads (Dubrulle
et al., 2001), with smaller somites anterior to the bead,
and a bigger one posterior to the bead.
Control of somite size
According to the clock and wavefront model, somite size
along the anteroposterior axis is determined by the distance traveled by the wavefront during one period of oscillation of the somitogenesis clock (whether it is the whole
somite or its boundaries that are specified). Supposing
that the PSM is at steady state, the distance traveled by
the wavefront is the same as the distance the PSM grows
posteriorly in the same interval. According to a model
of cell-autonomous decay of FGF8 mRNA defining the
wavefront (see above), for a given rate of decay of FGF8
mRNA and a given starting pool when cells join the PSM,
the speed of posterior progression of PSM sets the size of
somites. Thus a way to test that model (at a stage where
retinoic acid does not counteract FGF signaling) would
be to alter the speed of posterior progression of the PSM,
without affecting the rate of the clock; unfortunately there
does not seem to be a known way of doing that at present.
Manipulation of the wavefront has been achieved by
disruption of retinoic acid synthesis (Niederreither et al.,
1999, Maden et al., 2000, Diez del Corral et al., 2003,
Vermot & Pourqui´e, 2005, Vermot et al., 2005, Sirbu &
Duester, 2006), incubation with exogenous retinoic acid
(Moreno & Kintner, 2004), disruption of FGF signaling with a chemical inhibitor or grafting of FGF8-coated
beads (Sawada et al., 2001, Dubrulle et al., 2001, Delfini
et al., 2005), disruption of Wnt signaling (Nagano et al.,
2006), or grafting of Wnt-secreting cells (Aulehla et al.,
2003). Results consistently support the idea that increased
(respectively decreased) FGF8 or Wnt signaling pushes
the wavefront anteriorly, resulting in smaller (respectively
larger) somites, and that the opposite is true for retinoic
acid. The shift of sites of retinoic acid signaling during
early somitogenesis offers a complication of the clock and
wavefront model that has not yet been investigated in detail. It could be related to the difference in the segmen-
Unexplained phenomena
Another intriguing phenomena is the occurrence of
spatially periodic perturbations of somitogenesis after
heat shocks in chick (Primmett et al., 1988) and zebrafish
(Roy et al., 1999). These perturbations have been shown
to be linked to cell cycling in chick PSM (Primmett et al.,
1989). Based on local cell cycle synchrony in the PSM,
the authors proposed that segmentation is controlled by
the cell cycle, with a permissive phase of the cell cycle,
during which cells are competent to segment, and a later
instructive phase of the cycle, which induces cells to segment and to produce a diffusible molecule that induces
competent cells to also segment. This model is unique
in accounting for the periodicity of segmentation defects
after heat shocks (cells were proposed to be sensitive to
heat shocks only when at a particular phase of their cycle, which should occur at regular spatial intervals in the
PSM). The model proposed by Primmett et al. (1989) does
not call for an oscillatory gene expression pattern like that
of the Notch pathway, but it is also not incompatible with
it.
In summary, data seems to be lacking at present for the
formulation of a detailed model of clock and wavefront
interaction to control segmentation. Major unknowns are
the detail and kinetics of response of the FGF8 signaling
pathway to its ligand (and the reason for the asymmetric
response to FGF8 beads), the distribution of FGF8 protein in the PSM, the interaction between FGF and Wnt
signaling, the detail of clock-gene response to changes
in FGF8 signaling, molecular detail of joint control by
the clock and wavefront of targets that specify somites
or somite boundaries at the determination front, and finegrained mapping of gene expression patterns in the PSM
to somite positions (live imaging of reporter expression,
as performed by Masamizu et al., 2006, is a big step in
that direction).
11
4
Conclusion
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