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J. Anat. (2001) 199, pp.

143151, with 4 gures Printed in the United Kingdom 143


Derivation of the mammalian skull vault
GILLIAN M. MORRISS-KAY
Department of Human Anatomy and Genetics, University of Oxford, UK
(Accepted 3 April 2001)
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This review describes the evolutionary history of the mammalian skull vault as a basis for understanding its
complex structure. Current information on the developmental tissue origins of the skull vault bones
(mesoderm and neural crest) is assessed for mammals and other tetrapods. This information is discussed in
the context of evolutionary changes in the proportions of the skull vault bones at the sarcopterygian-
tetrapod transition. The dual tissue origin of the skull vault is considered in relation to the molecular
mechanisms underlying osteogenic cell proliferation and dierentiation in the sutural growth centres and in
the proportionate contributions of dierent sutures to skull growth.
Key words: Dermal bone; vertebrate evolution; neural crest ; cranial mesoderm.
i N1robic1i oN
The mammalian skull is the product of an evol-
utionary process during which 4 skeletal components
of independent origin have been progressively inte-
grated into a structure of exquisite structural and
functional complexity. Since three of these com-
ponents contribute to the mammalian skull vault, the
development of this structure is best understood in the
context of its evolutionary history. This review will
focus on the derivation of the skull vault with respect
to its evolutionary origins, its embryonic tissue
origins, and its pattern of growth. Recent observations
on the tissue origins of the skull vault and the genetic
control of its pattern of growth in mouse and human
will also be discussed; these have thrown light on both
developmental and evolutionary processes.
coxioNrN1s or 1nr vrr1rnr:1r siiii
The 4 components of the vertebrate skull are the
cartilaginous neurocranium, cartilaginous viscero-
cranium, dermal skull roof, and sclerotomal occipital
region. The way in which these 4 components
contribute to the skull is shown schematically in
Figures 1 and 2. Figure 1 combines some aspects of
the evolutionary sequence with an explanation of how
the 4 components contribute to mammalian skull
Correspondence to Professor G. M. Morriss-Kay at the Department of Human Anatomy and Genetics, South Parks Road, Oxford
OX1 3QX, UK. Tel. : j44 1865 272165\9; fax: j44 1865 272420; e-mail : morrissk!ermine.ox.ac.uk
structure. The following account is derived from
studies carried out over many decades of the past
century, summarised in the authoritative accounts of
Romer (1945), Goodrich (1958) and Janvier (1996).
Cartilaginous neurocranium (Figs 1, 2)
The neurocranium, which includes the skull base,
sensory capsules and the central part of the skull roof,
surrounds and protects the brain. The skull base is
formed from a series of cartilages either side of, and
rostral to, the notochord, whose tip lies just caudal to
the pituitary gland. It is closely associated with the
sensory capsules, which partially or completely sur-
round the olfactory epithelium, the eye, and the inner
ear. The cartilaginous parts of the neurocranium
undergo endochondral ossication in most species;
ossication has been lost in cartilaginous shes, but
the cartilaginous condition of the skull of lampreys is
considered to be primitive (Kardong, 1995). The
neurocranium is roofed by a vault of dermal bone
(Fig. 2b), which will be considered in detail below.
The occipital region, which surrounds the foramen
magnum, is formed from the sclerotome of the
occipital somites in a manner analogous to the
formation of vertebrae (compare the supraoccipital
cartilage and atlas vertebra in Fig. 2c). It is not
present in living or fossil agnathans ( jawless shes) or
Fig. 1. Components of the skull illustrated incrementally to show
their relationships and evolutionary changes. (A, B) Cartilaginous
neurocranium and viscerocranium in shes; (C) amphibian\
reptile\bird; (D) mammal. For clarity, the dermal skull roof is not
shown in AC.
cartilaginous shes, but appears to have arisen in
parallel in many bony shes (P. Ahlberg, personal
communication). Incorporation of the occipital ver-
tebrae into the skull was associated with the an-
nexation of the upper part of the spinal cord into the
brain, together with the rst 2 spinal nerves as cranial
nerves XI and XII.
Cartilaginous viscerocranium (Fig. 1bd)
The cartilaginous viscerocraniumsupports the feeding
structures, and, where present, the gills. It is formed as
a series of cartilaginous rods within the embryonic
branchial (pharyngeal) arches. Except in lampreys,
hagsh and cartilaginous shes, part or all of this
component of the skull undergoes endochondral
ossication.
The rst arch cartilages of our agnathan ancestors
were modied to form jaws, forming the palato-
quadrate (upper jaw) and Meckel s (lower jaw)
cartilages of gnathostomes ( jawed vertebrates; Fig.
1b). Further modication in tetrapods led to the loss
of parts of these structures, leaving only the ali-
sphenoid and the jaw articulation (quadrate and
articular) (Fig. 1c). In mammal-like reptiles, anterior
shift of the jaw articulation freed the quadrate and
articular bones to move with the second arch-derived
stapes (columella) into the middle ear for sound
conduction (Goodrich, 1958). The mammalian ali-
sphenoid forms the greater wing of the sphenoid bone,
which contributes a small part of the skull vault just
caudal to the orbit, and also underlies the basal part
of the frontal and parietal bones in the fetus (Iseki
et al. 1997) (Figs 1d, 2c). Second and third arch
cartilages contribute to the hyoid bone.
Mammalian rst arch neural crest is derived from
the midbrain and rostral hindbrain neural folds,
rhombomeres (r) 1 and 2 (Tan & Morriss-Kay, 1986;
Hunt et al. 1991; Serbedzija et al. 1992). In a quail-
chick chimaera study, Ko$ ntges & Lumsden (1996)
demonstrated that the rst branchial arch elements of
the viscerocranium are derived from specic neural
crest cell subpopulations within the rst arch crest.
Meckels cartilage is formed frommidbrain crest, with
the exception of its proximal (articular) region, which
is formed mainly from r1 and r2 neural crest. The
quadrate receives cells from posterior midbrain, r1
and r2 crest. Based on homology with the avian
pterygoid, they infer that the mammalian alisphenoid
is derived mainly from r1 and r2.
Dermal skull roof (Figs 1d, 2b)
The vertebrate skull roof is a very ancient structure,
forming a protective covering for the head in agnathan
fossil shes. It is absent in extant lampreys and
hagshes, which have neither endochondral nor
dermal bone. In ostracoderms, the armoured ag-
nathan groups considered to form the stem group for
gnathostomes (Janvier, 2001), dermal armour covers
the whole body; it is composed of plates in the skin
144 G. M. Morriss-Kay
Fig. 2. Endochondral and dermal bone components of the
vertebrate skull. (A) the skull base and sensory capsules. (B) the
basic dermal skull roof pattern in an early tetrapod: the bones that
survive in mammals are labelled, and the original skull vault series
is coloured. (C) E14n5 mouse embryo stained with alcian blue to
show the cartilaginous neurocranium and viscerocranium; the
orbitosphenoid cartilages (black arrow), each with a foramen for
the optic nerve, are attached to the presphenoid cartilage; the ear
ossicles are indicated by the white arrow. The cartilage labelled
alisphenoid only partly corresponds to the future alisphenoid bone;
its upper portion becomes overlaid by the dermal frontal and
parietal bones and disappears during early postnatal life. F, frontal ;
J, jugal (mammalian zygomatic) ; L, lacrimal ; Mx, maxillary;
N, nasal ; P, parietal ; Pm, premaxilla; pp, postparietal.
that have coalesced into larger elements in the head
but remain as small scales in the trunk, where
exibility is clearly required for propulsive movement
in animals that have not yet evolved paired ns.
Dermal bone diers from teeth, scales, feathers and
hair in being entirely derived from dermal mes-
enchyme, without any epithelial component. It has
been identied, together with enamel-like tissue and
cartilage, in tooth-like structures from the oral cavity
of conodont agnathan fossils dating from the late
Cambrian period, 515 million years ago (Sansomet al.
1992). It is formed entirely from bone that ossies
directly from mesenchyme in the deeper layers of the
dermis (intramembranous ossication). The process
of intramembranous ossication appears to be more
ancient than endochondral ossication.
The dermal skull roof covers not only the brain but
also the special sense organs, and extends laterally so
that in gnathostomes it reinforces the upper jaw. It is
continuous with the dermal bones of the palate on the
underside of the upper jaw. The dermal bones covering
Meckel s cartilage make an equivalent contribution to
the lower jaw, and both upper and lower jaw dermal
bone is the tooth-bearing part of the skull (premaxilla,
maxilla and dentary bones). It is interesting to note in
this context that in the absence of dermal bone, the
teeth of cartilaginous shes (chondrichthyans) are
anchored in the skin that covers the edges of the
mouth.
Figure 2(a, b) shows the positional relationship
between the neurocranium and skull roof in bony
shes, amphibians and stem reptiles. The space
between the cartilaginous skull base and the margins
of the dermal skull roof is lled by soft tissue
structures, including the muscles acting on the jaws,
the cranial nerves and blood vessels. In all vertebrates
except birds and mammals, the terms skull vault and
skull roof have dierent meanings. The basic tetrapod
skull vault is the middle section of the skull roof,
covering the brain. It is composed of paired frontal,
parietal and post-parietal bones, with which three
small bones (infratemporal, supratemporal and tabu-
lar) not represented in mammals are closely associated
(Fig. 2b). This pattern is derived fromthat of ancestral
lobe-nned shes (sarcopterygians), but in these the
frontal (and nasal) bones were represented by a
number of small plates near the rostral tip of the skull,
whereas the parietals and postparietals were already
large paired bones (Westoll, 1943). The frontal bones
of tetrapods were derived by coalescence of these
small bones, which then enlarged to cover much of the
forebrain (Ahlberg & Milner, 1994). They have
enlarged maximally in birds, in which they extend
over the whole forebrain and part of the cerebellum;
compared with the basic tetrapod pattern, the avian
parietal bones are much reduced and the postparietals
lost (Kardong, 1995). Mammalian frontal and parietal
bones are more equal in size, and both frontal and
parietal bones overlie the greatly expanded cerebral
hemispheres. The mammalian homologue of the
postparietals is the single interparietal, which lies over
the cerebellum and provides a dermal contribution to
the otherwise endochondral occipital bone.
Studies on skull development are much better
established in birds than in mammals because of the
technique of quail-chick embryonic tissue grafting (Le
Douarin, 1973). However, extrapolation of the results
of studies carried out in avian embryos to under-
standing mouse or human skull development and
growth must be regarded as provisional at best, since
avian and mammalian skull evolution diverged early
during evolution of the reptiles. Dierent patterns of
openings formed in the temporal regions of 2 reptilian
Derivation of the mammalian skull vault 145
lines: the line leading to birds (diapsids) formed 2
foramina whereas the mammal-like reptiles (syn-
apsids) formed a single temporal foramen (Goodrich,
1958).
A key change that took place during the evolution
of both mammals and birds was loss of the lateral
walls of the neurocranium, enabling the brain to
expand to ll the whole space under the dermal skull
roof. The temporal foramina in both groups merged
with the orbit and the squamosal bone became a
component of the neurocranium. In mammals the
squamosal also became part of the complex mam-
malian temporal bone, which incorporates the otic
capsule, the tympanic bone (derived from the reptilian
angular, a dermal component of the lower jaw) and
the 3 ear ossicles. It forms the upper jaw component
of the mammalian jaw articulation (temporo-
mandibular joint) and part of the zygomatic arch.
In summary, the evolutionary changes from the
early vertebrate to the mammalian skull have resulted
in a skull vault of complex origin. It is made up of the
original tetrapod dermal skull vault (frontals, parietals
and fused post-parietals), a bone from the temporal
region of the early vertebrate dermal skull roof
(squamosal), a small visceral arch contribution
(greater wing of the sphenoid) and a sclerotomal
contribution (the endochondral supraoccipital).
Growth of the skull vault, and of the brain beneath it,
depends on co-ordinated growth of all of these
elements. Each bone of the skull vault forms a
specialised brous joint (suture) with its neighbour.
The way in which interactions between the skull vault
bones contribute to growth within the sutures depends
on tissue interactions between the two juxtaposed
bones. These in turn are aected by the tissue origins
of the interacting bones in each suture.
1i ssir ori ci Ns or 1nr siiii
Contributions of neural crest and mesoderm
The cranial part of the vertebrate skeleton is unique in
its tissue origins. The axial and appendicular parts of
the skeleton are formed entirely from mesoderm, both
somitic (vertebrae) and lateral plate (limbs) ; the
developing skull is also partly mesodermal in origin,
but receives a substantial contribution from neural
crest (Le Douarin & Kalcheim, 1999, and references
therein). The role of neural crest in development of the
head is so fundamental that the origin of vertebrates
has been attributed to the invention of this tissue
(Gans & Northcutt, 1983). The origin of neural crest
as a vertebrate tissue, and its contribution to the
evolution of jaws, are discussed elsewhere in this issue
(Holland & Holland, 2001; Kimmel et al. 2001).
The evolutionary expansion of the cerebral hemi-
spheres of mammals is reected in developmental
specialisations. The neural plate is enlarged, and
neurulation does not proceed in a simple cranio-
caudal sequence. Instead, neural tube closure begins
at the hindbrain-spinal cord junction, progressing
caudally to form the developing spinal cord at the
same time as the broader cranial neural folds are
undergoing a more complex sequence of shape
changes to form the embryonic brain (Morriss-Kay,
1981). Neural crest cells migrate in a cranio-caudal
sequence as in other vertebrates, but the later closure
of the cranial neural tube in mammalian embryos has
the consequence that the most rostral crest cells
(midbrain and preotic hindbrain populations) migrate
from open neural folds (Adelmann, 1925). Crest cells
emigrating from the midbrain and caudal forebrain
neural folds form the frontonasal mesenchyme, which
migrates to cover the basal surface of the telencephalic
neuroepithelium (Tan & Morriss-Kay, 1985; Osumi-
Yamashita et al. 1994; Chai et al. 2000) (Fig. 3a),
from which the cerebral hemispheres are derived.
Together with the neural crest emigrating from the
rostral hindbrain (future r 1 and 2), it also forms the
mesenchyme of the facial processes (nasal, maxillary
and mandibular). This migration pattern is also
observed in birds (Noden, 1988; Couly et al. 1993).
There is general agreement that all of the dermal
bone that contributes to the viscerocranium is of
neural crest origin. This includes the mammalian
premaxilla, maxilla, zygomatic, squamosal, dentary
and tympanic bones, and their homologues in other
tetrapods (Chibon, 1967; Noden, 1988; Couly et al.
1993; Chai et al. 2000). However, the derivation of the
tetrapod skull vault series of bones (frontals, parietals
and post-parietals) is less clear. These bones dier-
entiate later than either cranial cartilage or the dermal
bones of the viscerocranium, and are dicult to trace
in cell lineage studies. Chibons (1967) lineage study
of amphibian neural crest identies only its con-
tributions to the jaws, branchial arches and anterior
skull base. Chick-quail chimaera studies are prob-
lematical because the skull vault bones have only just
begun to mineralise at the time the experiments are
terminated (E14), and the sutures are not clearly
formed at this stage. These observational diculties,
together with the small size of the avian parietals and
absence of postparietals, may explain the dierent
interpretation of quail-to-chick grafts of cranial neural
crest by Noden (1988) and Couly et al. (1993). Noden
regards the whole skull vault as mesodermal in origin,
146 G. M. Morriss-Kay
whereas Couly and colleagues interpret it as entirely
neural crest-derived.
Tissue origins of the mammalian skull vault
Cell and tissue lineage studies in mammalian embryos
have been uninformative for the skull vault because
they have relied on whole embryo culture (Tan &
Morriss-Kay, 1986; Serbedzija et al. 1992, Osumi-
Yamashita et al. 1994). Serbedzija et al. (1992) also
injected DiI into the amniotic cavity in utero, but did
not report the results at stages late enough to identify
skull vault bones, presumably because dilution of the
label still imposes a limit on the developmental time
period that can be followed. Avian data have therefore
been used for extrapolation to human skull vault
tissue origins. Given the early divergence of the
reptilian lines fromwhich birds and mammals evolved,
and the anatomical dierences between the skull roof
patterns of the 2 groups, it is important to dene the
tissue origins of the mammalian skull vault by direct
observation in a mammalian embryo.
Recently, a transgenic mouse has been created that
has a permanent neural crest cell marker. It combines
the Wnt1-Cre transgene, which is expressed only in
neural crest cells and in the midbrain\rostral hind-
brain, with a conditional LacZ reporter, R26R.
The reporter is only expressed when activated by Cre,
i.e. only in cells expressing Wnt1. Developmental
analysis of LacZ expression in this transgenic mouse
has revealed the contribution of neural crest cells to
the heart and aortic arches (Jiang et al. 2000) and has
conrmed its contribution to the viscerocranium,
including the teeth (Chai et al. 2000). The early
pathways (Fig. 3a) conrm the results of the previous
studies in rodents cited above, and also agree with
observations in birds (Noden, 1988).
Using this transgenic mouse, we have now analysed
the tissue origins of the developing skull vault. The
results (to be published in detail elsewhere) show that
the frontal and squamosal bones are neural crest-
derived, in contrast to the parietal and interparietal
bones, which are of mesodermal origin; the unossied
sutural membrane between the parietal bones is also
neural crest-derived (X. Jiang, S. Iseki, R.M.
Maxson, H.M. Sucov & G.M. Morriss-Kay, un-
published data). These observations are extrapolated
to the developing human skull in Figure 3b.
The distribution of neural crest and mesodermal
tissue in the developing skull vault has important
functional implications. Both major growth centres,
the sagittal and coronal sutures, are revealed as sites
in which there is a neural crest-mesodermal interface.
They full the criteria for denition as organising
centres, which according to Meinhardt (1983) are
formed at tissue interfaces that are sites of signalling
activity. There are also interesting evolutionary
insights from this new information. Taking the pineal
opening as the basis for determining parietal bone
homologies, neural crest-derived parts of the skull
roof of sarcopterygian shes are the peripheral
elements, i.e. those related to the upper jaw, and the
small rostral group of bones from which the frontal
and nasal bones are derived (Fig. 3c). On the basis of
these homologies, evolution of the tetrapod skull
vault can be seen to involve expansion of the neural
crest-derived component of the skull vault, which
expanded caudally to cover the forebrain. As dis-
cussed above, this expansion of neural crest-derived
bone was greater in the reptilian line leading to birds
than that leading to mammals.
i:11rrNs or crov1n i N 1nr x:xx:ii :N
siiii v:ii1
The patterns of growth in the mammalian and avian
skull vaults dier. In birds, ossication is relatively
late and the sutures between the dermal bones ossify
soon after growth ceases. In mammals, the coronal
(fronto-parietal) and sagittal (parietal-parietal)
sutures are major growth centres that are active
throughout the period of growth of the brain, which
lasts for many years in humans and other large
mammals with a long period of growth and matu-
ration. Bony fusion in these two sutures occurs late, if
at all. Remodelling, through the activity of osteoclasts,
is important for reshaping the bones as the cir-
cumference of the brain increases, and is an important
source of compensatory growth when the sutures
close prematurely (Wall, 1997). Osteoclast activity
begins early, and has been detected at prenatal stages
in the mouse skull (Rice et al. 2000).
The patterns of growth are not uniform in the
dierent sutures of the mammalian skull vault. In the
mouse, the apposing edges of the frontal bones show
a broad area of cell proliferation (Iseki et al. 1997)
(Fig. 4) ; in contrast, a discrete border of proliferating
osteogenic stem cells surrounds the parietal and
interparietal bones. The timing, and possibly also the
mechanism, of sutural closure also dier between
sutures. The human metopic (frontal-frontal) suture
undergoes bony fusion around the age of 6 y, and the
major contributions to subsequent skull growth are
made by the sagittal (interparietal) and coronal
sutures, the lambdoid suture contributing much less
Derivation of the mammalian skull vault 147
Fig. 3. Tissue origins of the skull vault. (A) Neural crest distribution in E9 mouse and E10 rat embryos (see text for sources) ; the cranial
ganglia are indicated in light green, other neural crest cells are dark green. (B) Extrapolation to the human skull of the observations on tissue
origins of the skull vault bones in the mouse, also showing the sutures and bones mentioned in the text (the premaxilla, maxilla and mandible
are not labelled) ; mesoderm-derived bones are indicated in beige. (C) Extrapolation of the observations on skull vault tissue origins to the
evolutionary changes in the skull during the transition from lobe-nned shes to tetrapods; dermal bones of uncertain tissue origin are
uncoloured. Di, diencephalon; e, eye; Eo, exoccipital ; Hy, hyoid; F, frontal ; FN, frontonasal mesenchyme; Ip, interparietal ; Md, mandibular
process; Mes, mesencephalon; Mx, maxillary process; N, nasal ; P, parietal ; Pt, petrous part of temporal bone (from otic capsule) ; Rh,
rhombencephalon; So, suoraoccipital ; Sq, squamous part of temporal bone; Tel, telencephalon; V, trigeminal ganglion; VII, facial ganglion;
Z, zygomatic bone ( jugal).
(Wall, 1997). Genetic control of growth in the sutures
has been revealed by identication of the mutations
causing premature sutural fusion (craniosynostosis;
Wilkie, 1997 and references therein). Specic acti-
vating mutations of FGFR1 and FGFR2 cause
craniosynostosis involving one or more sutures;
specic activating mutation of FGFR3 and haplo-
insuciency of TWIST, which encodes a transcription
factor essential for mesoderm development, are
associated specically with coronal synostosis (el
Ghouzzi et al. 1997; Howard et al. 1997; Muenke et
al. 1997).
All of the human mutations associated with
premature sutural fusion indicate that the sutures
between dermal bones are sites in which the balance
between osteogenic cell proliferation and dier-
entiation is under ne genetic control. In the develop-
ing mouse skull vault, Fgfr2 expression is associated
148 G. M. Morriss-Kay
Fig. 4. E16n5 mouse head, based on data from Iseki et al. (1997,
1999) : Fgfr2 is expressed in proliferating cells (in situ hybridisation
combined with anti-BrdU immunohistochemistry after 1-hour
BrdU uptake, blue) ; Fgfr1 is expressed in dierentiating osteogenic
cells (purple). The pattern of growth of the frontal bones (F) is
diuse, compared with the well dened proliferative zone around
the edges of the dierentiating parietal (P) and interparietal (IP)
bones. The underlying olfactory lobes and cerebral hemispheres are
outlined. cor, coronal suture; N, nasal bone.
with osteogenic cell proliferation, and Fgfr1 is
expressed in cells undergoing osteogenic dier-
entiation; expression of Fgfr3 is observed transitorily
in both populations (Iseki et al. 1999). Amouse model
for craniosynostosis due to a point mutation of Fgfr1
conrms the function of this gene in regulating
osteogenic dierentiation (Zhou et al. 2000). Twist
is expressed in the midsutural mesenchyme of the
frontoparietal (coronal) suture in both proliferating
and nonproliferating cells (Johnson et al. 2000).
Haploinsuciency of Twist is associated with loss of
the proliferating cells and premature fusion of the
coronal suture (Rice et al. 2000). Msx2 is expressed
around the edges of the parietal bones; comparison of
the eects of ectopic overexpression and inhibition of
the activity of this transcription factor suggests that
Msx2 prevents dierentiation and stimulates pro-
liferation of osteogenic cells in the cranial sutures
(Dodig et al. 1999). A single but extensive family is
known in which sagittal synostosis is associated with
mutation of MSX2 (Jabs et al. 1994).
Other pathways shown experimentally to partici-
pate in sutural growth include SHH and BMP (Kim
et al. 1998). Experiments in which the relationship
between the sutures and the underlying dura mater
have been manipulated in vitro suggest that TGFs
secreted by the dura are actively involved in the timing
of sutural fusion (Opperman et al. 1993; Greenwald et
al. 2000). None of these pathways has yet been found
to be abnormal in human craniosynostosis.
Human mutations have also revealed that the
sclerotomal (occipital) component of the skull is
under dierent genetic control from the dermal
component. Specic activating mutations of FGFR3
cause hypochondroplasia, achondroplasia and than-
atophoric dysplasia, all of which principally aect
endochondral bone formation and growth so their
eects are mainly on the long bones (Rousseau et al.
1994; Shiang et al. 1994; Ornitz, 2001 and references
therein). Except for hypochondroplasia, a mild form
of dwarsm, they also cause excessive growth of the
occipital region of the skull, reecting its distinct
histogenetic, embryological and evolutionary origin.
In the mouse, Fgfr3 is expressed at a higher level in the
cartilaginous regions of the E16 skull (occipital region
and alisphenoid) than in dermal bone (Iseki et al.
1999).
Less is known about genes responsible for the
process of ossication of the dermal bones. Cbfa1
is essential for both endochondral and intra-
membranous ossication (Komori et al. 1997).
Mutations of MSX2 and ALX4 have been detected in
patients with defective ossication specically of the
parietal bones (Wilkie et al. 2000; Mavrogiannis et al.
2001). Other human syndromes showing defective
calvarial ossication are known; knowledge of the
genetic control of skull vault ossication will benet
from identication of the mutations underlying these
syndromes. It remains to be seen whether dierent
molecular mechanisms are involved in the intra-
membranous ossication process of neural crest-
derived and mesodermal skull vault bones.
coNciisi oNs
The mammalian skull vault has a mixed develop-
mental tissue origin that reects its mixed evolutionary
origin. This complex history has functional con-
sequences for its pattern of growth, and for the genetic
control of the tissue interactions that are responsible
for maintaining a balance between osteogenic cell
proliferation and dierentiation in the two major
sutural growth centres. These insights raise substantial
newquestions: (1) howdoes the molecular basis of the
cellular signalling underlying sutural growth dier in
the sutures that are formed as tissue interfaces and
those that are not ; (2) how were changes in signalling
pathways in the sutures between the dermal bones of
Derivation of the mammalian skull vault 149
the skull roof of lobe-nned shes functionally
correlated with the phenotypic changes that gave rise
to the early tetrapod pattern; and (3) is the process of
ossication of neural crest-derived and mesodermal
bones governed by dierent genetic mechanisms? The
fact that these questions arise implies that the dual
tissue origin of the vertebrate skull vault has been of
major importance for its evolutionary plasticity.
:ciNovirbcrxrN1s
I thank Dr Per Ahlberg for Figure 3c and for
stimulating and informative discussions about the
text.
rrrrrrNcrs
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