J. Anat. (2001) 199, pp. 143–151, with 4 figures 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)

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 differentiation in the sutural growth centres and in

the proportionate contributions of different sutures to skull growth.

Key words : Dermal bone; vertebrate evolution; neural crest ; cranial mesoderm.

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.

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. : ­44 1865 272165}9; fax: ­44 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 ossification in most species ;

ossification has been lost in cartilaginous fishes, 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 fishes) or

Fig. 1. Components of the skull illustrated incrementally to show

their relationships and evolutionary changes. (A, B) Cartilaginous

neurocranium and viscerocranium in fishes ; (C ) amphibian}reptile}bird; (D) mammal. For clarity, the dermal skull roof is not

shown in A–C.

cartilaginous fishes, but appears to have arisen in

parallel in many bony fishes (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 first 2 spinal nerves as cranial

nerves XI and XII.

Cartilaginous viscerocranium (Fig. 1b–d )

The cartilaginous viscerocranium supports 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,

hagfish and cartilaginous fishes, part or all of this

component of the skull undergoes endochondral

ossification.

The first arch cartilages of our agnathan ancestors

were modified to form jaws, forming the palato-

quadrate (upper jaw) and Meckel ’s (lower jaw)

cartilages of gnathostomes ( jawed vertebrates ; Fig.

1b). Further modification 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 first 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 first branchial arch elements of

the viscerocranium are derived from specific neural

crest cell subpopulations within the first arch crest.

Meckel’s cartilage is formed from midbrain 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 fishes. It is absent in extant lampreys and

hagfishes, 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 ) E14±5 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

flexibility is clearly required for propulsive movement

in animals that have not yet evolved paired fins.

Dermal bone differs from teeth, scales, feathers and

hair in being entirely derived from dermal mes-

enchyme, without any epithelial component. It has

been identified, 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 (Sansom et al.

1992). It is formed entirely from bone that ossifies

directly from mesenchyme in the deeper layers of the

dermis (intramembranous ossification). The process

of intramembranous ossification appears to be more

ancient than endochondral ossification.

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 fishes (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

fishes, amphibians and stem reptiles. The space

between the cartilaginous skull base and the margins

of the dermal skull roof is filled 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 different 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 from that of ancestral

lobe-finned fishes (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. Different 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 fill 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 fibrous 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 affected by the tissue origins

of the interacting bones in each suture.

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 reflected 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 differ-

entiate later than either cranial cartilage or the dermal

bones of the viscerocranium, and are difficult to trace

in cell lineage studies. Chibon’s (1967) lineage study

of amphibian neural crest identifies 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 difficulties,

together with the small size of the avian parietals and

absence of postparietals, may explain the different

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 from which birds and mammals evolved,

and the anatomical differences between the skull roof

patterns of the 2 groups, it is important to define 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

confirmed its contribution to the viscerocranium,

including the teeth (Chai et al. 2000). The early

pathways (Fig. 3a) confirm 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 unossified

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 fulfil the criteria for definition 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 fishes 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.

The patterns of growth in the mammalian and avian

skull vaults differ. In birds, ossification 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

different 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 differ 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-finned fishes 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 identification of the mutations

causing premature sutural fusion (craniosynostosis ;

Wilkie, 1997 and references therein). Specific acti-

vating mutations of FGFR1 and FGFR2 cause

craniosynostosis involving one or more sutures ;

specific activating mutation of FGFR3 and haplo-

insufficiency of TWIST, which encodes a transcription

factor essential for mesoderm development, are

associated specifically 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 differ-

entiation is under fine genetic control. In the develop-

ing mouse skull vault, Fgfr2 expression is associated

148 G. M. Morriss-Kay

Fig. 4. E16±5 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 differentiating osteogenic

cells (purple). The pattern of growth of the frontal bones (F) is

diffuse, compared with the well defined proliferative zone around

the edges of the differentiating 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 differ-

entiation; expression of Fgfr3 is observed transitorily

in both populations (Iseki et al. 1999). A mouse model

for craniosynostosis due to a point mutation of Fgfr1

confirms the function of this gene in regulating

osteogenic differentiation (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).

Haploinsufficiency 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 effects of ectopic overexpression and inhibition of

the activity of this transcription factor suggests that

Msx2 prevents differentiation 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 TGFβs

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 different genetic control from the dermal

component. Specific activating mutations of FGFR3

cause hypochondroplasia, achondroplasia and than-

atophoric dysplasia, all of which principally affect

endochondral bone formation and growth so their

effects 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 dwarfism, they also cause excessive growth of the

occipital region of the skull, reflecting 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 ossification of the dermal bones. Cbfa1

is essential for both endochondral and intra-

membranous ossification (Komori et al. 1997).

Mutations of MSX2 and ALX4 have been detected in

patients with defective ossification specifically of the

parietal bones (Wilkie et al. 2000; Mavrogiannis et al.

2001). Other human syndromes showing defective

calvarial ossification are known; knowledge of the

genetic control of skull vault ossification will benefit

from identification of the mutations underlying these

syndromes. It remains to be seen whether different

molecular mechanisms are involved in the intra-

membranous ossification process of neural crest-

derived and mesodermal skull vault bones.

The mammalian skull vault has a mixed develop-

mental tissue origin that reflects 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 differentiation in the two major

sutural growth centres. These insights raise substantial

new questions: (1) how does the molecular basis of the

cellular signalling underlying sutural growth differ 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-finned fishes functionally

correlated with the phenotypic changes that gave rise

to the early tetrapod pattern; and (3) is the process of

ossification of neural crest-derived and mesodermal

bones governed by different 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.

I thank Dr Per Ahlberg for Figure 3c and for

stimulating and informative discussions about the

text.

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