1 Developmental Neurobiology, National Institute for Medical Research, The
Ridgeway, Mill Hill, London NW7 1AA, UK
2 Laboratory of Developmental Neurogenetics, NINDS, NIH, Bethesda, MD 20892,
USA
3 Department of Cell Biology, School of Medicine, Vanderbilt University,
Nashville, TN 37232, USA
Author for correspondence (e-mail:
vpachni{at}nimr.mrc.ac.uk)
Accepted 9 June 2003
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SUMMARY |
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Key words: Somite, Myogenesis, Chondrogenesis, Homeobox
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Introduction |
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Experimental and gene-expression data strongly indicate that the generation
of somite periodicity and the establishment of rostrocaudal polarity takes
place before segment-border formation in the apparently homogenous PSM.
Studies of knockout mice have confirmed that the Notch/Delta signaling pathway
has a crucial role in establishing both temporal periodicity in the PSM and
rostrocaudal polarity in somite primordial (reviewed by
Pourquie, 2001;
Saga and Takeda, 2001
).
Evidence of the molecular nature of the oscillator has emerged recently from
studies that demonstrate lunatic fringe implements periodic inhibition of
Notch signalling to establish a negative feedback loop, which controls the
cyclic expression of genes in the presomitic mesoderm
(Dale et al., 2003
).
The correct formation, patterning and differentiation of somites requires
the activity of at least several genetic pathways. Wnt signals from the
surface ectoderm are implicated in somite epithelialisation
(Borycki et al., 2000), and the
paraxis bHLH transcription factor is necessary for the formation of epithelial
somites (Burgess et al., 1996
;
Johnson et al., 2001
).
Mutations in the Notch pathway disrupt not only the patterning of the PSM
but also anteroposterior polarity of somites
(Barrantes et al., 1999). Foxc1
and Foxc2 are both required for the formation of segmented somites, and may
function by interaction with the Notch signalling pathway in the anterior
presomitic mesoderm (Kume et al.,
2001
). Whereas mutations in Eph, Ephrin and cadherin genes in mice
have not revealed phenotypes - in contrast to zebrafish
(Durbin et al., 1998
) and frog
embryos (Kim et al., 2000
) -
affecting somite boundaries, a dominant-negative papc (cadherin) molecule
disrupts the epithelial organization of cells at the segmental borders between
somites in transgenic mice (Rhee et al.,
2003
).
A large body of evidence, from both in vitro and in vivo experiments
(reviewed by Brent and Tabin,
2002), indicates that antagonism between different signals from
adjacent tissues is required to subdivide the somite into distinct
compartments: the ventral mesenchymal sclerotome that generates the
chondrogenic axial skeleton, and the dorsal epithelial dermomyotome that forms
the skeletal muscles of the trunk, limbs and tongue. Sonic hedgehog (SHH) and
noggin are thought to be the ventralising signals for sclerotome induction,
and WNT proteins are involved in establishment of the dorsal domain of the
somite. BMP signals, originating in the lateral mesoderm, negatively regulate
the spatial and temporal activation of somitic myogenesis
(Reshef et al., 1998
) and
positively regulate lateral somitic cell fates
(Pourquie et al., 1996
;
Tonegawa et al., 1997
). It is
likely that noggin-mediated antagonism of BMP signaling is required for both
myotomal and sclerotomal development
(McMahon et al., 1998
). There
is also evidence that SHH changes the competence of target somitic cells to
respond to BMPs to induce chondrogenesis
(Murtaugh et al., 1999
).
The induction of Pax1 and Pax9 gene expression by SHH is
necessary for vertebral and rib formation
(Peters et al., 1999), and
Foxc2 is required for sclerotome proliferation
(Winnier et al., 1997
).
Targeted mutagenesis of the MRF family of bHLH transcriptional activators
(MYF5, MYOD1, myogenin, MRF4) in the mouse has revealed an essential, but
different, role for members of this gene family in the formation of skeletal
muscle (reviewed by Arnold and Braun,
2000
), and Pax3 and Myf5 are required for the
expression of Myod1 in the trunk
(Tajbakhsh et al., 1997
). Long
range signaling by SHH has a role in the induction of Myf5 gene
expression in the dorsal somite
(Gustafsson et al., 2002
).
We have previously described the isolation of the MEOX sub-family of
homeobox transcription factors (Candia et
al., 1992; Candia et al., 1996). Both Meox1 and
Meox2 genes have characteristic expression in the somites of the
paraxial mesoderm in vertebrate embryos. Meox1 mutant mice display
defects restricted to sclerotomal derivatives, the vertebrae and ribs are
fused (S.S., B.M., C.W., V.P. and H.A., unpublished). By contrast, the
Meox2 mutation produces a phenotype that affects the development of
the limb muscles (Mankoo et al.,
1999
). Meox2 is required for the expression of
Pax3 RNA in migrating limb myoblasts; and also for the induction of
Myf5 gene expression, but not that of Myod1, in limb
myoblasts. As each single Meox gene mutation affected only a subset of somitic
derivatives, despite a largely overlapping expression pattern, this raised the
possibility the two genes have overlapping functions and are capable of
compensating for each others absence. To investigate the combined function of
the MEOX subfamily of homeoproteins, we crossed mutations for both
Meox1 and Meox2. The complete absence of Meox gene activity
resulted in unexpected and severe defects in somite development. The axial
skeleton and most skeletal muscles were not formed. Somite epithelialisation
and rostrocaudal somite patterning were also disrupted, as was the maintenance
of somite boundaries. Both Meox1 and Meox2 genes were also
required for the normal differentiation of cells derived from both the
sclerotome and dermomyotome. We propose that the concerted activity of the two
Meox genes is an essential component of the genetic circuitry that regulates
somitogenesis.
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Materials and methods |
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Determination of recombinant embryonic stem cells and genotyping of
animals
Details on the molecular identification of the transgene insertion of
Meox1 and the determination of all mutant genotypes can be obtained
on request.
Histology, in situ hybridisation and skeletal preparations
For histology, embryos or tissues were fixed in Bouin's fixative,
dehydrated and embedded in paraffin wax. Serial sections (8 µm) were
stained with Haematoxylin and Eosin. For semi-thin sections the tissues were
embedded in epoxy resin and sections were cut with a glass knife. Whole mount
in situ hybridization was performed as previously described
(Mankoo et al., 1999). For
cryosectioning, embryos were postfixed in 4% paraformaldehyde, equilibrated in
30% sucrose and embedded in OCT. Skeletal preparations of newborn pups were
produced using a combination of Alcian Blue and Alizarin Red staining.
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Results |
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Skeletal preparations of animals carrying a single wild-type Meox1 allele (Meox1+/-, Meox2-/-) displayed defects affecting the axial skeleton; the ribs were normal, and vertebral defects were only apparent at posterior levels (Fig. 1C,G). Animals with a single wild-type Meox2 allele (Meox1-/-, Meox2+/-) were more seriously affected; ribs were present but with fusions, and vertebral bodies were split at the lumbar level, while posterior to the pelvic girdle poorly differentiated cartilaginous elements were seen in place of vertebrae (Fig. 1B,F). Skeletal preparations of double mutants (Meox1-/-,Meox2-/-) revealed a striking phenotype, these animals lacked a normal vertebral column, which was largely replaced by two strips of fused cartilage, corresponding in position to the neural arches. There was no cartilage or bone present in the ventral midline the location of vertebral bodies; and, although centres of ossification were observed at the cervical and thoracic level of the axial skeleton, neither normal vertebrae nor ribs were observed (Fig. 1D). In addition, no skeletal or cartilaginous elements were detectable at or posterior to the pelvic girdle (Fig. 1D,H) The occipital skull bones, which are somite derived, were hypoplastic, whereas other cranial bones were unaffected (not shown). These observations demonstrate that strong dosage dependent interactions between Meox1 and Meox2 are essential for the formation of the axial skeleton; each gene can compensate, to a differing extent, for the absence of the other.
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We also examined the expression of Dll1, a member of the Notch
signalling pathway, which is expressed in the presomitic mesoderm and the
posterior half of newly formed somites and is required for epithelialisation
of somites and establishment of their anteroposterior polarity
(Hrabe de Angelis et al.,
1997). In E9.5 Meox1; Meox2 double mutants, expression of
Dll1 in the presomitic mesoderm was unaffected, but expression in the
newly formed somites was greatly reduced and restricted dorsally
(Fig. 4G,H; data not shown). As
visualised by Dll1 expression, the myotomes of anterior somites in
Meox1; Meox2 double mutants were fused ventrally but separated
dorsally (Fig. 4I,J). This
analysis is consistent with a defect in epithelialisation of somites in double
mutants. Furthermore, it indicates that in the absence of Meox proteins, the
specification of the posterior somitic halves is not maintained resulting in
somitic fusions and abnormal patterning of DRGs and spinal nerves.
To determine whether the observed abnormalities in somite polarity were a
consequence only of defects in specification of the posterior half of somites,
we examined the expression of Epha4. At E9.5, Epha4
expression is located in two stripes: a broad posterior stripe at the most
anterior border of the presomitic mesoderm and an anterior stripe in the
anterior half of the most newly formed somite
(Barrantes et al., 1999)
(Fig. 4K). In all mutants, the
posterior stripe of Epha4 expression in the presomitic mesoderm was
not altered. In mutants with only one wild-type Meox allele, the anterior
stripe of expression was present but less refined than in controls
(Fig. 4L,M); however, in the
Meox1; Meox2 double homozygotes, the expression corresponding to the
anterior half of the prospective somite was ablated
(Fig. 4N), indicating that
patterning of the anterior half of the somite is also defective in the Meox
mutants.
Sclerotome differentiation but not sclerotome specification is
perturbed in mutant embryos
To further examine somitic differentiation in Meox-deficient animals, we
analysed the expression of Pax1 and Pax9, two genes that are
expressed in the sclerotome and are critical for normal axial skeleton
development (Peters et al.,
1999). In E9.5 Meox1; Meox2 double mutants, Pax1
mRNA was absent from the paraxial mesoderm throughout the anteroposterior
axis, while branchial arch and limb bud expression were unaffected
(Fig. 5A-F). In addition,
Pax9 expression was dramatically reduced, particularly in the
posterior somite halves, resulting in a continuous, albeit anteriorly
truncated, band of reduced expression along the anteroposterior axis of the
mutant embryo (Fig. 5G-J),
further supporting a defect in somite compartmentalisation.
|
Failure of the molecular programme for skeletal myogenesis in the
absence of Meox genes
To study the mechanisms underlying the skeletal muscle defects, we examined
the expression of essential regulators of myogenesis in the dermomyotome and
myotome, such as Pax3 and Myf5
(Maroto et al., 1997;
Tajbakhsh et al., 1997
). In
E9.5 Meox1; Meox2 double mutant embryos, the expression of
Pax3 was severely reduced in paraxial mesoderm with only a weak
signal observed in the ventrolateral region of somites at the level of the
forelimb bud (Fig. 6A,B). This
signal is likely to correspond to the precursors of limb myoblasts that
colonise the limbs of Meox1; Meox2 mutants. This finding
indicates that despite the failure of differentiation of an epithelial
dermomyotome, at least a certain degree of myoblast specification takes place
in Meox double mutants. A similar reduction was observed in the expression of
Pax7 (Fig. 6C,D), an
additional marker of dermomyotome (Jostes
et al., 1990
). The dramatic attenuation of Pax3 and
Pax7 expression in Meox1; Meox2 mutants indicates that Meox
genes function as crucial regulators of genetic pathways upstream of
Pax3 and Pax7 gene activation.
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Discussion |
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Multiple functions of the Notch pathway have been proposed
(Barrantes et al., 1999;
Takahashi et al., 2000
)
initially in the presomitic mesoderm (prior to any Meox gene function) to
segment the mesoderm and establish rostrocaudal polarity of presumptive
somites; and subsequently in nascent somites to regulate somite patterning and
boundary formation. The polarity of the somites was disrupted in
Meox1; Meox2 mutants as a consequence of defects in
patterning of both anterior and posterior halves, with an associated
downregulation of Dll1 and Epha4 expression, a phenotype
shared with the Dll1 mutants. Our observations indicate that aspects
of the phenotype of the Meox1; Meox2 double mutants are partly (via
Dll1) explained by a perturbation in the Notch signalling
pathway. The irregular and different size of somites is similar to that
observed in Notch1 mutants
(Conlon et al., 1995
), which
also supports our interpretation that the Meox genes are involved in the
correct transition of cells from the presomitic mesoderm into somites.
The phenotype of Meox1/Meox2 mutants resembles aspects of the
Foxc1/Foxc2 compound mutants
(Kume et al., 2001); however,
the effect of the Foxc mutations seems to impact at the anterior presomitic
mesoderm prior to Meox gene expression, indicating that Foxc genes do not
function directly to activate Meox expression.
The most dramatic aspect of the Meox double mutant phenotype is the severe
loss of both ventral (vertebrae and ribs) and dorsal (skeletal muscles) somite
derivatives. The sclerotomal defect in Meox1; Meox2 mutants
can be traced back to early defects in the specification and patterning of the
ventral somite, as revealed by reduced expression of Pax1, Pax9 and
Twist. This interpretation is further supported by the abnormal
dorsal restriction of paraxis expression in the newly formed somites. The
absence of Pax1 induction in the somite phenocopies the effect seen
in the absence of hedgehog signalling in the mouse embryo
(Zhang et al., 2001) and
suggests that a function of Meox genes may be to mediate the response of
somitic cells to hedgehog signals. The severe defects in skeletal muscles were
also due to early defects in the patterning and differentiation of the
myogenic derivatives of the dorsal somite, as revealed by alterations in
Pax3, Pax7, Twist, Myf5, myogenin and paraxis expression.
Chondrogenesis and myogenesis require Meox activity
Our data indicate an essential requirement for Meox activity in both
chondrogenesis and myogenesis in the somite, differentiation pathways that
have been considered to be mutually exclusive. One mechanism by which this may
occur is based on the requirement for Pax gene activity in chondrogenesis
(Pax1 and Pax9) (Peters
et al., 1999) and myogenesis (Pax3 and Pax7)
(Tajbakhsh et al., 1997
;
Seale et al., 2000
) and our
observation that both Meox genes are co-expressed with all four of these Pax
genes in somitic mesoderm. We have previously demonstrated that in migrating
limb myoblasts, which express only Meox2 and not Meox1,
Meox2 is upstream of Pax3
(Mankoo et al., 1999
). In the
present study, we have shown that the absence of Meox gene activity from
somitic mesoderm disrupts the expression of all four somite-expressed Pax
genes. Therefore, the differentiation of somite derivatives into cartilage and
muscle requires the Meox-dependent expression of Pax gene function.
Interestingly, we have also observed that Meox proteins can interact with Pax1
and Pax3, indicating that there may be cooperativity in the action of these
proteins during somitogenesis (Stamataki
et al., 2001
).
Possible mechanisms for Meox function
The patterning and differentiation of somites is governed by complex
interacting signals that originate in adjacent tissues: neural tube, lateral
plate mesoderm and surface ectoderm
(Borycki and Emerson, 2000;
Correia and Conlon, 2000
;
Gossler and Hrabe de Angelis,
1998
). It is clear that the competition between antagonistic
signals is largely responsible for the patterning of somites and the
subsequent fate of the cells in the different somitic domains (reviewed by
Brent and Tabin, 2002
). These
signals include SHH, noggin, WNT and BMP proteins. Signalling by WNT and SHH
molecules, which have been shown to act at a distance greater than the length
of a somite in vitro (Fan et al.,
1997
; Fan et al.,
1995
), appears to be responsible for the subdivision of the somite
into dorsal and ventral subdomains respectively. Furthermore, Sfrp2 is a
SHH-inducible WNT antagonist that can block the dermomyotome-inducing
properties of WNTs in explants (Lee et
al., 2000
) and, conversely, GAS1 may function as a
WNTinduced inhibitor of SHH activity in the dorsal somite
(Lee et al., 2001
). BMP
signals can negatively regulate the spatial and temporal activation of somitic
myogenesis (Reshef et al.,
1998
) and sclerotome induction by SHH
(McMahon et al., 1998
), and
positively regulate lateral somite fates
(Pourquie et al., 1996
;
Tonegawa et al., 1997
). The
suppression of BMP signals by noggin is probably required for both myotomal
and sclerotomal development (McMahon et
al., 1998
). There is also evidence of interactions of these
signals, for example, SHH regulates competence of cells to respond to BMP. In
the absence of SHH, BMP signals result in lateral plate gene expression, but
following prior exposure to SHH cells respond to BMP by inducing
chondrogenesis in explant cultures
(Murtaugh et al., 1999
). As
the dorsoventral and mediolateral subdivision of the somite is affected
profoundly in the Meox1;Meox2 mutants, it suggests that these genes
may function to provide competence to the somitic cells to respond to one or
more of these signals.
Whereas the formation of somite boundaries and the initial establishment of
rostrocaudal polarity in the presomitic mesoderm are genetically separable
(Nomura-Kitabayashi et al.,
2002), and take place prior to the expression of both Meox genes,
it is clear from our studies that the maintenance of boundaries and polarity
in newly formed somites are not separate events and require the activity of
both Meox genes. Evidence that interactions between compartments occur during
somitogenesis is provided by the observed vertebral defects in
Myf5;paraxis double mutants, which indicate an indirect role for
Myf5 in the development of the axial skeleton (A. Rawls, personal
communication). Furthermore, the defects in the lateral sclerotome derivatives
in Pax3 mutant mice may result from a disruption in the interaction
between Pax3-expressing dermomyotome and the non-expressing
sclerotome (Henderson et al.,
1999
). Whereas the initiation of expression of Pax3 is
independent of paraxis, the maintenance of Pax3 expression in the
dermomyotome requires paraxis
(Wilson-Rawls et al., 1999
).
Therefore, in the dorsoventral dermomyotome paraxis may function as an
intermediate in the regulation of Pax3 expression by Meox genes.
The extreme nature of the Meox1; Meox2 double mutant phenotype may be explained by one of two models: (1) The perturbation of a single early event in somite formation that results in failure of somitic cells to respond to one or more inductive signals from surrounding tissues; or (2) a synergistic perturbation of several somite patterning and differentiation pathways, with a compounding effect on the defects occurring in individual somite compartments. The expression pattern of the Meox genes is consistent with both hypotheses - which are not mutually exclusive, in any case - and much work will be required to resolve the complex combinatorial effect of these genes. Overall our studies demonstrate that Meox homeobox genes function in a co-ordinated manner to regulate critical processes that effect the development of somites.
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ACKNOWLEDGMENTS |
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Footnotes |
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