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DEVELOPMENTAL DYNAMICS 209:139–155 (1997)
REVIEW ARTICLE
Developmental Patterning and Evolution
of the Mammalian Viscerocranium:
Genetic Insights Into Comparative Morphology
SHIGERU KURATANI,* ISAO MATSUO, AND SHINICHI AIZAWA
Department of Morphogenesis, Institute of Molecular Embryology and Genetics,
Kumamoto University School of Medicine, Kumamoto 860, Japan
ABSTRACT
The vertebrate cranium is generally classified into the neurocranium and the
viscerocranium. The latter is derived from the
neural crest and so is the prechordal portion of
the neurocranium. A view we favor considers the
prechordal neurocranium as the premandibular
component of the viscerocranium, and the vertebrate skull to consist of the neural crest-derived
viscerocranium and the mesodermal neurocranium. Of these developmental units, only the
viscerocranium appears to have completely segmented metamerical organization. The Hox code
which is known to function in specification of the
viscerocranium does not extend rostrally into the
mandibular and premandibular segments. By genetic manipulation of rostrally expressed nonHox homeobox genes, the patterning mechanism
of the head is now demonstrated to be more
complicated than isomorphic registration of the
Hox code to pharyngeal arches. The phenotype by
haplo-insufficiency of Otx2 gene, in particular,
implies the premandibular cranium shares a common specification mechanism with the mandibular arch. Our interpretation of the metamerical
plan of the viscerocranium offers a new scheme
of molecular codes associated with the vertebrate head evolution. Dev. Dyn. 209:139–155,
1997. r 1997 Wiley-Liss, Inc.
Key words: cranium; homeobox genes; pharyngeal arch; mandibular arch; trabecula; comparative embryology; evolution
INTRODUCTION
Morphological and Developmental View of the
Vertebrate Cranium
The cranium comprises the most complicated part of
the vertebrate body and has long stimulated questions
as to how this structure is constructed and how it
develops during ontogeny. These questions are natur 1997 WILEY-LISS, INC.
rally bound to its segmental plan and its evolutionary
origin. The concept of segmental vertebrate head stems
from Goethe (1790), Oken (1807), and Owen (1866) who
speculated that the vertebrate skull was composed of a
certain number of fused vertebrae (Fig. 1A). This view
is now accepted only in the occipital region that arises
from somites (reviewed by Noden, 1988; Couly et al.,
1993), but the basic concepts of the metamerism and
metamorphosis of the cranium are still valid in the
pharyngeal portion of the skull since branchial arch
cartilages are also repeating units along the anteroposterior axis.
Anatomically, the vertebrate cranium is divided into
the brain case (neurocranium) and the pharyngeal arch
skeletons (viscerocranium; Fig. 1B; see e.g., Portmann,
1976; and Torrey and Feduccia, 1979). These neuroand viscerocrania contain cartilaginous elements comprising the chondrocranium. The dermal exoskeleton
covers the entire chondrocranium as dermatocranium
and is also divided dorsoventrally into neuro- and
viscerocranial elements. The neurocranium is regarded
as the rostral continuation of the vertebral column
containing the central nervous system. To this the
cartilaginous sensory capsules, the nasal, optic, and
otic capsules are attached. The main portion of the
neurocranium is the sphenoid bone and the dermal
calvarium, and the caudal portion is the occipital,
which is thought to be the secondarily attached vertebrae (Fig. 1B; Fürbringer, 1897; reviewed by de Beer,
1937; Goodrich, 1930). The viscerocranium is composed
of a series of repeated bar-like cartilages within the
pharyngeal arches. The rostral-most element is called
the mandibular arch skeleton and is altered to function
as upper and lower jaws in gnathostomes.
Experimental embryology has revealed that the vertebrate head contains two types of mesenchyme as the
*Correspondence to: Shigeru Kuratani, Department of Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto
University School of Medicine, 4-24-1, Kuhonji, Kumamoto, Kumamoto 860, Japan. E-mail: [email protected]
Received 26 September 1996; Accepted 25 February 1997
A
eye
inner ear
nasal
organ
B
neurocranium
orbital
region
otic
capsule
nasal
capsule
notocord
pharynx
dermocranium
gill
mandibular hyoid
arch
arches
arch
viscerocranium
C
orbital
cartilage
nasal
capsule
quadrate
cartilage
otic
capsule
occipital
cartilage
vertebrae
trabecula
Meckel's
cartilage
hyoid
arch
branchial
arches
Fig. 1. Morphological plans of the cranium. A: Idealistic vertebrate as
segmental organism, redrawn from Owen (1866). B: Generally accepted
architecture of the vertebrate cranium, redrawn from Torrey and Feduccia
(1979). The skull of gnathostomes consists of neurocranium, viscerocranium, and dermatocranium. The neurocranium contains the brain inside
and the viscerocranium covers the pharynx. The latter further consists of
metamerical series of cartilage bars of which the rostralmost element is
parachordal
cartilage
notocord
changed into the jaw. Sensory capsules are attached to the neurocranium. These cranial elements are cartilaginous and the whole chondrocranium is covered by dermal elements, the dermatocranium. Note the
caudal portion of the neurocranium is actually the fused vertebrae, the
occipital. C: Early embryonic chondrocranium of a lizard, redrawn from
Torrey and Feduccia (1979). Note the position of prechordal cartilage, or
the trabecula.
MORPHOGENESIS OF THE MAMMALIAN SKULL
source of the cranium, i.e., the neural crest-derived
ectomesenchyme and mesoderm. Mesodermal mesenchyme is dorsally located as cranial paraxial mesoderm
lateral to the neural tube, and ventrally, the ectomesenchyme resides in the pharyngeal arches thereby forming pharyngeal arch skeletons (reviewed by Noden,
1988; Köntges and Lumsden, 1996; Couly et al., 1996).
Thus, all the viscerocranial elements (both cartilaginous and dermal) are of neural crest-origin (Le Lièvre
and Le Douarin, 1975; reviewed by Noden, 1988; Couly
et al., 1993).
Comparative embryology can, to some degree, predict
mesenchymal origins of mammalian cranial elements
(see Fig. 2B). The origin of dermal bones in the calvarium still remains a matter of controversy (Le Lièvre,
1978; Noden, 1988; Couly et al., 1993). As for the origin
of laryngeal cartilages in amniotes, Gegenbaur (1898;
also see Starck, 1979) assumed their homologies with
caudal branchial arch cartilages, which seems unlikely.
It has been shown in avian embryos that these cartilages including tracheal rings are derived from the
lateral mesoderm; they are more likely to represent
neomorphic structures (Noden, 1983b). In the mammalian cranium, therefore, the caudalmost pharyngeal
arch cartilage appears to be the caudal part of the hyoid
body that belongs to the arch 3 region.
On the Trabecula Cranii
The mesodermal mesenchyme does not exist rostrally
beyond the level of the hypophysis; the notochord,
which is essential for chondrogenesis of mesodermal
tissue, also does not exist in this area (Pourquie et al.,
1993). Data obtained in avian experiments confirmed
that the prechordal neurocranium originates from the
neural crest (Le Lièvre and Le Douarin, 1975; reviewed
by Noden, 1988; Couly et al., 1993). In mammalian
skulls, nasal septum, lachrymal, presphenoid, basisphenoid (in part?), and anterior portions of orbitosphenoid
and frontal bones are thought to belong to the prechordal region; a part of the frontal bone may also be
derived from the neural crest. The junction between the
prechordal and chordal cranium lies approximately at
the level of the cephalic flexure of the brain and dorsum
sellae of the mammalian skull (Fig. 2B). Simultaneously, this junction corresponds to the site of orbital
cartilage development, the anterior-most cartilage element that develops underneath the neural tube (Kuratani, 1989). In many vertebrates, the cartilaginous
prechordal neurocranium develops from an element
called the trabecular cartilage that originally arises as
a pair of bar-like cartilages (Fig. 1C; Rathke, 1839;
reviewed by de Beer, 1931, 1937).
The neural crest-origin of the trabecula in various
vertebrates (Stone, 1926; Raven, 1931; Andres, 1949;
Wagner, 1949, 1959; Noden, 1978; Hall and Hörstadius,
1988; Couly et al., 1993), its topographical location,
morphology, and the metamerical organization of cranial nerves suggest that this cartilage may represent a
premandibular component of the viscerocranium that
141
belongs to the same segment as the ophthalmic nerve,
as was first stated by Huxley (1874; reviewed by
Goodrich, 1930; de Beer, 1931, 1937; also see Stadmüller, 1936). Although several arguments exist, we
favor this view based on the recent genetic data stated
below.
Considering an ammocoete larva of the lamprey as a
hypothetical intermediate state, de Beer (1931) viewed
the mucocartilage in the upper lip as the trabecula
homologue and tried to explain how the premandibularly located branchial cartilage could have moved into
the position of the prechordal neurocranium. He assumed a great change in the topographical relationship
between the neural tube and the cartilaginous component to explain how the trabecula had come into contact
with the nasal epithelium, hypophysis, and the forebrain. The common anatomical plan of the rostral-most
neural tube is shared by a closely related group of
vertebrates, the amphioxus (Lacalli et al., 1994); it is
hardly conceivable that such a substantial change took
place in the gnathostome evolution. Instead, Holmgren
and Stensiö (1936) and others identified the ammocoete
trabecula as the cartilage that develops as the rostral
continuation of the parachordal, not the mucocartilage
juxtaposed to the mandibula. The mucocartilage that
de Beer (1931) called the trabecula does not seem to
arise from the neural crest either (reviewed by Janvier,
1993).
The ectomesenchyme forming the trabecula may
have been originally located in close association with
the rostral-most part of the gut (Allis, 1938), similar to
what is the case for the other pharyngeal arch skeletal
elements. In most of the early vertebrate embryos, the
rostral-most portion of the gut is seen as the preoral gut
located dorsoanterior to the mouth. The vertebrate
mouth is formed in the ventral aspect of the pharynx
and caudal to the trabecular mesenchyme (Fig. 3A).
The position of the preoral gut is very close to the
hypophysis, nasal epithelium, forebrain, and the ophthalmic nerve. Kastschenko (1887) reported vestigial
pharyngeal pouches on the side wall of Seessel’s pouch.
A reasonable hypothesis, then, is to assume that the
trabecular cartilage may have grown out and slid
rostrally beneath the forebrain, not swung rostrally as
de Beer proposed, and became the prechordal neurocranium (Fig. 3B). The incorporation of the trabecula into
the formation of the neurocranium is probably associated with the mouth formation in ancestral vertebrates, earlier than the formation of the biting jaw. The
absence of dorsoventral articulation of the trabecula
cranii in gnathostomes would mean that it was attached to the brain before articulation arose (also see
Allis, 1938).
The Hox Code in the Patterning of the
Viscerocranium
In 1828 Karl Ernst von Baer proclaimed the pharyngular stage as the bottleneck in vertebrate development; all the vertebrates arrive at this stage by differ-
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Fig. 2. Hypothetical genetic codes of the viscerocranial patterning and
embryonic composition of the mammalian skull. A: The Hox code is
present in the second arch and more caudal levels. This code is parallel to
that in the neuraxis, which is indicated by bars with the same colors as the
mesenchymal code. The posterior portion of the first arch skeleton may be
patterned by the default state of the Hox code, whereas the anterior lower
portion (dentary, D) by Otx2. Crest cells from the caudal midbrain which
express Otx2 fill the mandibular arch (Osumi-Yamashita et al., 1994).
A3–6, pharyngeal arches; H, hyoid arch; M, the first arch; ot, otocyst; PM,
premandibular segment. B: Origins of viscerocranial elements in mamma-
lian skull. Colors indicate the origin of ectomesenchyme shown in (A).
White represents elements whose origins are uncertain. Gray elements
develop from mesodermal mesenchyme in avian embryos (Couly et al.,
1993). Otic capsule (ot) is derived from both mesoderm and neural crest
(Noden, 1988). as, Alisphenoid; bo, basioccipital; bs, basisphenoid; eo,
exoccipital; f, frontal; i, jugal; in, incus; ip, interparietal; j, jugal; lc,
lachrymal; m, malleus; mn, mandibula; mx, maxilla; nc, nasal capsule; ns,
nasal; par, parietal; pl, palatine; pm, premaxilla; ps, presphenoid; pt,
pterygoid; so, supraoccipital; sq, squamosal; st, stapes; ty, tympanic;
vom, vomer.
Fig. 3. Morphological plan of the vertebrate cranium—a hypothesis.
A: Generally, the skull is assumed to be composed of dorsal neurocranium and ventral viscerocranium. The neurocranium in this scheme is
subdivided into mesodermal chordal cranium and neural crest-derived
prechordal cranium. B: In the present review we propose that the
premandibular visceral arch element (5 the trabecula) was present in
association with the preoral gut in the ancestral vertebrate. This cartilage
element would have developed close to the olfactory epithelium and the
hypophysis and located dorsoanterior to the mouth that opened on the
ventral aspect of the pharynx. C: Developmental plan of the gnathostome
cranium. The thick dotted line indicates the interface between the
neuro- and viscerocrania in the concept of the present scheme, which
simultaneously represents the interface between the mesodermal and
crest-derived portions of the skull. Visceral arch skeletons except the
premandibular one are divided into dorsal and ventral halves. The mandibular arch skeleton acquired masticatory capability. The trabecula has been
changed into a secondary neurocranium. Consistent with the ancestral
state, the trabecula maintains close association with the nasal epithelium.
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ent means and develop different features, but there is
something in this particular stage that appears invariant morphologically. It is during this period that the
collinear nested pattern of Hox gene expressions, the
Hox code is established along the axis (reviewed by
McGinnis and Krumlauf, 1992; and by Krumlauf, 1993;
Prince and Lumsden, 1994; Mark et al., 1995); those
located on the more 38 side within the gene cluster are
expressed from the more anterior levels of the body axis
and extend caudally (Fig. 2A). In the trunk, the Hox
genes are expressed in provertebrae, and shifts or
modification of the Hox code result in the re-specification of vertebrae (Balling et al., 1989; Le Mouellic et al.,
1992; Jegalian and De Robertis, 1992; Pollock et al.,
1992; McLain et al., 1992; Lufkin et al., 1992; Charité et
al., 1995; Suemori et al., 1995). Consistent results have
also been obtained by the retinoic acid-induced respecification of vertebrae, which is roughly associated
with the shift of the Hox code in the provertebrae
(Kessel and Gruss, 1991; Kessel, 1992). It has been
shown recently that multiple disruptions of paralogous
Hox genes can result in more profound and wideranging transformations of vertebrae (Horan et al.,
1995) or deletion of elements, probably reflecting the
involvement of paralogues in different phases of cell
proliferation (Condie and Capecchi, 1994).
Each pharyngeal arch skeletal element also achieves
its specific shape through development under the Hox
code. This segmental metamorphosis has been suggested to be determined in the premigratory neural
crest that extends from the mid- to hindbrain neurectoderm (Wagner, 1959). In the hindbrain, the anterior
border of each Hox gene expression domain coincides
with the anterior sulci of odd-numbered rhombomeres
(r3, r5, and r7), the segmented bulges of the hindbrain
(Hunt et al., 1991; Fig. 2A). The Hox code in the caudal
head region involves the first five (Hox-1 to 5) paralogues and is also present in the pharyngeal ectomesenchyme and epithelia in a pattern parallel to that in
the hindbrain (Hunt et al., 1991; Prince and Lumsden,
1994). Importantly, there is no Hox gene expressed in
the arch 1 segment (Fig. 2). Such Hox gene expression
patterns may be conserved in diverse vertebrate classes
(e.g., Frasch et al., 1995; Morrison et al., 1995), with each
cognate being linked with specific segmental identity
(Burke et al., 1995; van der Hoeven et al., 1996). Crest
cell influx into pharyngeal arches is the principal basis
of this coincidence in segmental registration between
rhombomeres and pharyngeal arch mesenchyme (Köntges and Lumsden, 1996; Couly et al., 1996).
The origin and migration patterns of hindbrain crest
cells are not as strictly segmented on the neuraxis as
had initially been thought (Sechrist et al., 1993; Niederländer and Lumsden, 1996; also see Lumsden et al.,
1991; and Graham et al., 1993, 1994; Osumi-Yamashita
et al., 1996). Especially, the postotic arch mesenchyme
has extensively overlapping origin on the posterior
hindbrain, though the pharyngeal Hox code exists in
this region (Kuratani and Wall, 1992; Shigetani et al.,
1995). The arch-specific Hox gene expressions, there-
fore, cannot be ascribed only to the rhombomeric origin
of the crest cells; these cells can autonomously continue
to express the same Hox genes with the original neurepithelium as seen in r4-derived cells destined for arch 2
(Kuratani and Eichele, 1993), but the expression can
also be regulated by an environment that the crest cells
encounter (Saldivar et al., 1996; Hunt et al., 1995; also
see Couly et al., 1996). Nevertheless, being expressed in
a nested pattern Hox genes are believed to participate
in the patterning of branchiomeric structures such as
skeletons, and in other pharyngeal derivatives as well
(Manley and Capecchi, 1995).
In the viscerocranium Hoxa-2 disruption is the only
example that causes homeotic transformation of the
arch skeletons (see below) and no other single Hox gene
disruptions have resulted in the transformation
(Chisaka and Capecchi, 1991; Chisaka et al., 1992;
Lufkin et al., 1991; Ramirez-Solis et al., 1993; reviewed
by Manak and Scott, 1994 and by Mark et al., 1995). In
contrast to the trunk region, paralogue Hox genes have
the anterior expression limits at the same rhombomeric
levels (reviewed by Krumlauf, 1993): evolutionary multiplication of Hox clusters and resultant redundancy in
function among paralogues (e.g., Holland et al., 1994;
Manak and Scott, 1994) may have limited the apparent
homeotic function to Hoxa-2 by disruption of a single
gene in the viscerocranium; in the second arch Hoxa-2
is major (Rijli et al., 1993; Gendron-Maguire et al.,
1993; Mark et al., 1995).
Concerning the apparently limited homeotic function
of cephalic Hox genes, to be kept in mind is the fact that
transformation of rhombomeres has also been reported
only between r2/3 and r4/5 on administration of retinoic
acid (Marshall et al., 1992) and in Hoxa-1 gain of
function (Zhang et al., 1994). Likewise, only the ectopic
cartilage with the mandibular arch identity can be
generated within the second arch by the neural crest
transplantation (Noden, 1978, 1983a). The caudal head,
therefore, seems to possess only a limited number of
rhombomeres and branchiomeres that could homeotically transform. Of note is that there are only three
segments of pharyngeal arch skeletons in the mammalian cranium (excluding the trabecula), of which the
third is only vestigial as a part of the hyoid complex.
More caudally, pharyngeal arches are associated with
somites dorsally, but Hox genes are more or less involved in somitomeric specifications (e.g., Lufkin et al.,
1991; Ramirez-Solis et al., 1993), with phenotypes
comparable to those in the trunk. Though the Hox code
may play essential roles in the patterning of branchiomeric structures in principle, many ambiguities remain.
Evolution of the Mammalian
Mandibular Arch Skeleton
The mammalian cranium possesses several unique
features that are not seen in other vertebrates. In
particular, the first arch skeleton has gone through an
extensive modification during evolution. Mammals arose
as a subgroup of fossil synapsid amniotes. Nevertheless, comparative morphology with extant reptiles or
MORPHOGENESIS OF THE MAMMALIAN SKULL
145
Fig. 4. Comparative morphology and evolution of the middle ear
skeletons. A–C: Comparative morphology. Both the mandibular and hyoid
arches possess simple skeletons that are divided into dorsal and ventral
elements in shark (A). In the mandibular arch, the dorsal cartilage is called
palatoquadrate (pq), and the ventral the cartilage of Meckel (Mk). The
caudal ends of these cartilages articulate with each other as quadrate (q)
and articular (a), respectively. The dorsal element of the hyoid arch
skeleton, the hyomandibula (hm), functions as suspensorium. In the
modern reptile, this cartilage element is used as sound-transmitting
apparatus in the middle ear, as the columella auris (col; B). The dorsal
process or the epipterygoid (ept) of the palatoquadrate originates from the
suprapharyngeal element of the first arch. The same cartilage develops
into the ala temporalis (at) in the mammal (C) and forms a secondary
cranial base as a part of the sphenoid bone (see Fig. 5). The quadrate and
articular cartilages are separated from the main portion of the first arch
cartilage and translocated into the middle ear as incus and malleus,
respectively. Mammalian homologue of the columella auris is called
stapes (st). The ethmoid (et) and goniale (gn) are homologous with the
angular (an) and prearticular (pa) in the reptilian skull (B). Note the
reptilian tympanic membrane develops in the upper jaw region while that
of the mammal belongs to the lower jaw. ch, Ceratohyal; lh, laterohyal; Rc,
Reichert cartilage; tm, tympanic membrane. Modified from Goodrich
(1930). D,E: Evolution of the middle ear from cynodont (D) to mammalian
(E) conditions. Cynodont lower jaw (D) possesses a dermal element, the
angular, whose ventrocaudal portion is expanded as the reflected lamina
(rl); this portion is changed into the tympanic (et) of mammals (E). The
articular of this animal attaches to the angular and develops the retroarticular process (rp) which alters itself into manubrium mallei (mm). d, Dentary;
q, quadrate; qj, quadratejugal. After Allin (1975).
sauropsids has provided the following intriguing insights into the evolution of the mandibular arch skeleton.
In the viscerocranium, one of the anterior elements
(the second including the trabecula) acquired the masticatory ability in the earliest gnathostomes (Fig. 3). The
mandibular arch skeleton is divided into two halves,
the dorsal part or the palatoquadrate and the ventral
part or the cartilage of Meckel. Conspicuous is the
establishment of the middle ear in this skeleton of
mammals. Mammals possess three ear ossicles—
malleus, incus, and stapes, while amphibians and
sauropsids have only one—the columella auris (Fig. 4B,
C). Of those, stapes is equivalent to the columella auris
of sauropsids and to hyomandibular cartilage of fish,
the dorsal element of the hyoid arch skeleton. As for the
mammal-specific ossicles, malleus, and incus, their
direct equivalencies apparently do not exist in other
vertebrates. Reichert (1837) first demonstrated by comparative observations of various embryos that these
two cartilages arose as mesenchymal condensations
articulating with each other as caudal portions of both
palatoquadrate and Meckel’s cartilages. Thus, malleus
was homologized with articular, and the incus with the
quadrate of sauropsids. This finding was further
strengthened by Rabl (1887), Gaupp (1912), and by
Fig. 5. Morphology and evolution of the mammalian cranial wall. Left: Comparative anatomy
of the cavum epiptericum. Reptiles possess the original cartilaginous cranial wall, and a part of the
mandibular arch skeleton, the epipterygoid, is located lateral to the cranial wall. The epipterygoid
covers the extracranial space, the ‘‘cavum epiptericum’’ (Gaupp, 1902), containing the trigeminal
ganglion. In mammals, the cartilaginous cranial wall diminishes and the secondary cranial wall is
established with visceral elements (ala temporalis equivalent to the reptilian epipterygoid, and a
newly formed dermal element, the alisphenoid) ventrolateral to the primary one. Note the identical
topographical relationships of elements between the two animals. The mammalian cavum
epiptericum containing the trigeminal ganglion thus combined lateral to the original cranial cavity.
Primary and secondary cranial cavities are delineated by a meningeal membrane. Modified from
Goodrich (1930). Right: Comparison of the cranial side walls in the early cynodont fossil (above)
and the modern mammalian skull (below). Note the expansion of the alisphenoid (as) and
incorporation of the trigeminal nerve foramina (V1 for the ophthalmic, V2 for the maxillary, V3 for
the mandibular nerve). as, Alisphenoid; occ, occipital; p, parietal; pal, palatine; po, postorbital; pr,
perioticum; sq, squamosal.
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KURATANI ET AL.
MORPHOGENESIS OF THE MAMMALIAN SKULL
147
Fig. 6. Cranial defects caused by the Otx2 haplo-insufficiency. Cranial
defects by the haplo-insufficiency are variable (Matsuo et al., 1995). A–E:
Dorsal cranial views of the wild-type (A) and Otx2 haploid deficient mice
(B, C). F–J: Ventral aspects of the same skulls represented in A–E. A and
F show normal configuration of the newborn murine skull. B and G show
the lightest anomaly in the mutant skull. No major changes are seen
except for an ectopic transverse bar of bone (arrowheads) developing on
the basisphenoid (bs) and foramina in the skull base (asterisk). The arrow
indicates an ectopic junction between the incus (in) and alisphenoid (as).
The mandible (dentary) of this specimen appears normal. In the skull
shown in C and H the transverse bar is more extensive than in B,
possessing a central cartilaginous nodule (asterisk). The cranial base is
split into two halves at the midline (H). Note that middle ear ossicles
derived from arch 1 (in, m) and the tympanic (ty) have shifted towards the
midline in association with the arrested development of the dentary. More
heavily deformed skulls are shown and in these embryos the dentary is
missing. The eye is also missing on the right side of one embryo (D, I) and
on both sides of the other (E, J). The middle ear components derived from
the mandibular arch have shifted farther medially. Arrows in A indicate the
alisphenoid-incus junction as seen in anamniotes and sauropsids (Fig.
4B, C). In embryo E, the mandibular arch elements have shifted extremely
medially and the tympanic has almost fused to become a transverse bar.
Note that in the same skull, the stapes (st), the hyoid arch derivative, has
developed in the normal place. The nasal capsule was lacking in this
embryo, leaving the nasal septum (ns). acc, Alicochlear commissure; bs,
basisphenoid; cc, cochlear capsule; f, frontal; fo, optic foramen; g,
goniale; j, jugal; m, malleus; Mc, Meckel’s cartilage; mx, maxilla; ns, nasal
septum; os, orbitosphenoid; pa, processus alaris; pl, palatine; pm,
premaxilla; ps, presphenoid; pt, pterygoid; Rc, Reichert cartilage; sq,
squamosal.
Goodrich (1930) with various evidence from comparative zoology.
In addition to the middle ear ossicles, to be noted
about the mammalian mandibular arch skeleton is the
metamorphosis of the sphenoid (Fig. 5). The original
cartilaginous neurocranium is diminished and replaced
by dermal bones in mammals. Gaupp (1902) noted that
the large wing of the mammalian sphenoid or its
cartilaginous precursor, ala temporalis, is equivalent to
a part of the palatoquadrate (5 reptilian epipterygoid),
and is secondarily attached to the central stem to
function as a cranial wall below the trigeminal ganglion
(Fig. 5).
According to Presley and Steel (1976), the alisphenoid is a dermal bone secondarily attached to the ala
temporalis, representing a neomorphic structure. The
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KURATANI ET AL.
Figure 6.
mammalian skull possesses the secondary cranial wall
lateral to the original one, and has expanded the
cranial cavity by incorporating the extracranial space,
the cavum epiptericum. Evolutionarily, the incorporation of the cavum can be traced through the synapsid
fossils (Fig. 5; reviewed by Kemp, 1982; Moore, 1981;
Kermack and Kermack, 1984). In addition, a series of
dermal elements belonging to the maxillar segments of
mammals have been expanded to form medially the
secondary palate, establishing the separation of air
passage from the oral cavity.
Reichert’s view had a number of opponents until
recently (reviewed by Strickland et al., 1962; Hanson et
al., 1962; Jarvik, 1980; also see Williams and Warwick,
1990). The controversy was primarily centered on the
ambiguity of the boundary between ectomesenchymal
domains since the first pharyngeal slit of mammals has
been extensively modified. As noted above, the Hox
gene expression pattern at early stages is delineated in
(Continued.)
terms of single arches, and disruption of a Hox gene is
expected principally to affect only those skeletal elements that are derived from a single ectomesenchymal
population. Indeed, by disruption of the Hoxa-2 gene,
the second arch of the mutant mouse skeleton took the
shape of the mandibular arch; a homeotic transformation (Rijli et al., 1993; Gendron-Maguire et al., 1993).
Malleus and incus were duplicated, being consistent with
the hypothesis that these are mandibular arch components, and the duplication also occurred in parts of the
sphenoid proving them to be palatoquadrate derivatives (Fig. 4C). Although the final proof has to be made
by long-term neural crest labeling which is technically
not available at the moment, Reichert’s homology of ear
ossicles is consistent with the result of Hoxa-2 disruption as is Gaupp’s in the evaluation of the alisphenoid.
The Hoxa-2 disruption approximates the genetic code
of the second arch skeleton to that of the first or the
‘‘default state’’ (Mark et al., 1995), and the phenotype is
MORPHOGENESIS OF THE MAMMALIAN SKULL
consistent with the scheme of Hox code-mediated metamorphosis of the viscerocranium. However, the anterior
portion of the mandibular arch, the dentary, was never
duplicated in this mutant. This suggests the possibility
that morphogenetic identity of the mandibular arch is
not determined only by Hox gene expression.
Otx2 Gene in Mandibular Arch Patterning
Several homeobox genes have been reported to be
expressed in region-specific manners in the rostral
head. Mouse cognates of Drosophila head gap genes
ems and otd (Cohen and Jürgens, 1990; Finkelstein and
Perrimon, 1990) have been isolated as Emx1, 2, and
Otx1, 2, respectively (Simeone et al., 1992). Like Hox
genes, these genes are expressed in a nested pattern on
the neuraxis rostral to the mid-hindbrain boundary.
Remarkably, the Otx2 expression domain is posteriorly
limited by the mid-hindbrain junction. The gene is also
expressed transiently within the mandibular arch ectomesenchyme as well as in the frontonasal region (Ang
et al., 1994).
Disruption of the Otx2 gene was performed by several
groups independently (Acampora et al., 1995; Matsuo
et al., 1995; Ang et al., 1996). The homozygous mutation
resulted in embryonic lethality around 9.0 dpc with the
truncation of the neuraxis anteriorly at the level of
rhombomere 2; this is probably due to Otx2 expression
in cells destined for the prechordal mesoderm as suggested by the same defect in Lim-1 deficiency (Acampora et al., 1995; Shawlot and Behringer, 1995; Matsuo
et al., 1995; Ang et al., 1996). Heterozygous mice with
disrupted Otx2 alleles showed an interesting craniofacial haploinsufficiency phenotype (Matsuo et al., 1995).
The phenotypes are reminiscent of otocephaly in man
and rodents with a graded series of severity. Most
striking was the loss of the dentary, and this was
associated with disturbed development of mesencephalic trigeminal neurons; these neurons evolved to
control the force of mastication, and agnatha which
does not have a jaw also lacks the neurons (Sarnat and
Netsky, 1981). The Otx2 defects did not extend more
posteriorly into the middle ear components. The sphenoid was always present though sometimes deformed
possibly due to defects of the premandibular segment
(see below). Notable is a connection between the incus
and alisphenoid that sometimes developed in Otx2
haploid mutants; the connection is reminiscent of the
solid palatoquadrate in ancestral forms (Fig. 6).
Phenotypes in the mandibular arch skeleton found in
Otx2 haploid- and Hoxa-2 disruptions are complementary to each other: in the Hoxa-2 mutant, only the
posterior component of the mandibular arch skeleton
was duplicated, while in the Otx2 heterozygous mutant,
only the anterior component, the dentary, tended to be
lost. The ectomesenchyme in this arch originates both
from rhombencephalic and mesencephalic regions
(Osumi-Yamashita et al., 1994; also see Le Lièvre, 1974;
Köntges and Lumsden, 1996). In addition, Dil labeling
studies have suggested that crest cell populations origi-
149
nated from different levels of neuraxis do not intermingle evenly but are, rather spatially dissociated from
each other within the first arch (Osumi-Yamashita et
al., 1994, 1996; Imai et al., 1996). The mandibular arch
mesenchyme may thus be subdivided into at least two
domains. The posterior components involving the malleus, incus, tympanic, sphenoid (in part), and pterygoid
may be patterned after a default state, whereas the
dentary is patterned by Otx2.
Homeobox Genes Involved in the Formation
of Mandibular Arch Skeletons
Analyses of mutant mice by gene targeting have now
clarified the roles of many genes related to cranial
development (Kurihara et al., 1994; Lohnes et al., 1994;
Mendelsohn et al., 1994; Matzuk et al., 1995; Kaufman
et al., 1995; Dietrich and Gruss, 1995; Luo et al., 1995;
Schorle et al., 1996; Zhang et al., 1996; Mansouri et al.,
1996), although the redundant function among related
genes inherently obstructs this approach. Phenotypes
were usually more limited than was expected from their
expression patterns. Of those, mutant phenotypes of
several homeobox genes are worth considering in the
context of this review. gsc, originally identified as the
gene actively expressed in the Xenopus organizer (Cho
et al., 1991), is expressed in the anteriormost mesoderm
during gastrulation and in the posterior half of the
mandibular arch (Gaunt et al., 1993). However, gscdeficient mice showed only atrophies of the tympanic
bone and ala temporalis (Yamada et al., 1995; RiveraPérez et al., 1995); both are mandibular arch-derivatives uniquely specified in mammals as noted above.
MHox is a paired-like homeobox gene and expressed in
undifferentiated ectomesenchyme of all the pharyngeal
arches (Cserjesi et al., 1992; Kuratani et al., 1994), but
the disruption of the gene in mouse leads to malformation of mandibular arch components alone (Martin et
al., 1995); an ectopic process developed on Meckel’s
cartilage, and ala temporalis, the jugal, tympanic, and
squamosal diminished. Msx1, an msh-type homeobox
gene, is strongly expressed in the distal portion of the
mandibular arch (MacKenzie et al., 1991) and its
disruption leads to the partial loss of the malleus and
arrested development of teeth (Satokata and Maas,
1994). Dlx-2, a Distalless-related homeobox gene is
expressed in the mandibular and hyoid arches (Porteus
et al., 1991; Price et al., 1991; Robinson et al., 1991;
Robinson and Mahon, 1994), and its disruption causes
the rearrangement of dermal elements (Qiu et al.,
1995). Some of the ectopically developed dermal bones
in this mutant are reminiscent of the dermocranial
pattern of synapsids (reviewed by Kermack and Kermack, 1984).
The secondary palate is another mammalian specific
feature derived from the mandibular arch as stated. Its
development was disturbed and a cleft palate was
produced by disruptions of Hoxa-2, Dlx-2, and Msx1.
Defects in the alisphenoid by Dlx-2, gsc, and MHox
mutations is consistent with the assumption that this
150
KURATANI ET AL.
Fig. 7. Cranial defects due to the Otx2 haplo-insufficiency (continued).
One of the most severely affected skulls is showed on the left. In this
specimen the prechordal cranial base failed to fuse rostrally from the level
of basisphenoid (bs), and yielded a large fossa (**). This separate portion
located at the prechordal level. The pair of rod-like cartilages (*) and the
fossa are reminiscent of the trabecula (tr) and hypophysial fenestra (hy),
respectively, in the chondrocranium of Ambystoma at 12 mm stage
(Winslow, 1898). Note the extension of the notochord (nt) in this animal.
For abbreviations, see Figure 6.
bone element primarily belongs to the mandibular
ectomesenchyme. As noted earlier, comparative embryology suggested that in mammals the original connection between the ala temporalis and incus was lost
leaving only a thread of condensed connective tissue
(Presley and Steel, 1976). This connection partly chondrifies in Otx2 and Dlx-2 mutants, though differently
(Fig. 6; Qiu et al., 1995).
The Otx2 and Hoxa-2 genes are expressed in an axial
level-specific manner in multiple cell lineages. Expressions of Dlx-2, MHox, Msx1, and gsc are more likely to
be associated with mesenchymal tissue in the pharynx
at later onset, and may developmentally locate downstream of axial level-specification. Their disruptions
caused very limited deformities which correspond more
or less to mammalian specific features of skeletons. The
presence of closely related genes that are expressed in
overlapping domains (s8, Dlx paralogues, Msx2) should
be kept in mind. At the same time, evocation of regulatory mechanisms that recruited these genes for mammal-specific patterning and evolution of the skull might
be suggested.
Patterning of the Premandibular Segment
In addition to the mandible, major defects by Otx2
haplo-insufficiency were found in premandibular skeletons, and were often associated with loss of the nasal
Fig. 7.
Fig. 8. Metamerical composition of the vertebrate viscerocranium and
the genetic codes (hypothesis). Above: In the hypothetical ancestor of
vertebrates the viscerocranium consisted of a series of atypical pharyngeal arch skeletons with no articulations. The mouth opened, in this
animal, on the ventral aspect of the pharynx, caudal to the rostralmost
segmental element. In this ancestor, the collinear expression of Hox
genes and anteriorly restricted expression of head homeobox genes, Otx
and Emx genes (Simeone et al., 1992; Boncinelli et al., 1993; Matsuo et
al., 1995; Yoshida et al., 1997; Suda et al., 1996), may have existed.
Importantly, the mandibular cartilage-equivalent (the second cartilage
element from the front) is contributed by the rostral-most ectomesenchyme as well as by the second. Below: In vertebrates the compartmentrestricted Hox code and the anterior homeobox genes have enabled
segment-specific homeosis between mandibular and hyoid arches. Hox
code exists in r3 and caudally (r2 is secondarily involved as shown by
thinner broken line; Prince and Lumsden, 1994), while the Otx2 expression domain has its caudal boundary at the mid-hindbrain boundary. Note
that arches 4 to 6 do not develop pharyngeal arch skeletons in mammals
(shown by open lines). The thick dotted line roughly indicates the
boundary between regions in which Hox code is involved in the viscerocranial (branchiomeric) and the somitomeric specifications. The mandibular
arch skeleton develops from two populations of ectomesenchyme carrying distinct genetic codes. Note that blank ectomesenchyme of the
mandibular arch represents the ‘‘default’’ state; its developmental identity
is mimicked by the second arch in Hoxa-2 disruption (Rijli et al., 1993;
Gendron-Maguire et al., 1993) and is not affected by Otx2 haploinsufficiency (Matsuo et al., 1995).
MORPHOGENESIS OF THE MAMMALIAN SKULL
Fig. 8.
151
152
KURATANI ET AL.
capsule (Fig. 6). In the cranial base the presphenoid
was often deformed, the region was suggested to be of
neural crest-origin (Couly et al., 1993) and to belong to
the premandibular segment as stated above. The posterior part of the basisphenoid, on the other hand, was
not affected. This part of the skull base is most likely to
be of mesodermal origin as suggested by avian embryology and comparative embryology (Fig. 2B; Kuratani,
1989). Sometimes Otx2 heterozygous embryos possessed a pair of separate cartilage rods in place of the
nasal septum (Fig. 7). The overall configuration resembled the platybasic skull base; the morphology of
bar-shaped cartilage is widespread in anamniotes and
is also shared by sauropsid chondrocrania at earliest
stages but not in mammals (see de Beer, 1937). In
addition, the defects were associated with specific loss
of the ophthalmic branch of the trigeminal nerve that
belongs to the same segment as the premandibular
skeleton (Matsuo et al., 1995).
The nasal capsule largely consists of the lateral nasal
wall including various processes (turbinals), and the
medial nasal septum, the direct derivative of the trabecula (Bellairs, 1958). The former appears to derive
from the mesenchyme within the lateral nasal prominence and the latter from the medial nasal prominence
(see Osumi-Yamashita et al., 1997). The lack of the
nasal wall in Otx2 heterozygotes was always associated
with the loss of nasal epithelium while the nasal
septum was always present, though slightly deformed
(Fig. 6; Matsuo et al., 1995). Strikingly similar defects
have been reported in Pax 6 mutants in mouse (Kaufman et al., 1995) and in the rat (Osumi-Yamashita et
al., 1997). In this mutant, a ‘‘unicorn’’-shaped medial
cartilage bar representing the nasal septum developed,
but no trace of lateral walls was found with the lack of
nasal epithelium. Thus, it seems likely that the patterning mechanisms are different between the nasal septum and the nasal wall. Both Pax 6 and heterozygote
Otx2 mutants have eye defects, but lack of the eyeball
does not affect the development of the nasal cartilage
elements (Bellairs, 1958). Coextensive loss of nasal
epithelium and the lateral wall suggests the epithelialdependent development of this cartilage as stated by
Thorogood (1988).
Premandibular skeletal elements such as the lachrymal and anterior part of the frontal were not substantially deformed in Otx2 heterozygotes, though primary
defects cannot definitively be discriminated from secondary defects by morphological criteria. Nevertheless,
absence of any defects in the cranial base caudal to the
hypophysial level along with the specific loss of the
ophthalmic branch of the trigeminal nerves strongly
suggests that Otx2 functions in a branchial segment
specific manner which is in accordance with the segmental scheme of the viscerocranium, and is responsible for
the formation of the premandibular segment (Matsuo
et al., 1995).
Chordate Cranial Evolution From Morphology
and Molecules
Master patterning genes such as Otx2 and Hox genes
are expressed along the axis in a conserved nested
pattern, which may be universal throughout the animal
kingdom (reviewed by Slack et al., 1993; and by Holland and Garcia-Fernàndez, 1996). These genes may
act only to demarcate relative positions, and under this
demarcation specification of any particular structure is
diverged in each group of animals. The vertebrate body
plan is not simple, nor is the genetic code associated
with this plan. It is also highly possible that the
assignment of each unit may only be based upon
topographical relationships with no profound plan.
We believe that the prechordal neurocranium represents a viscerocranial element as stated above (Figs. 3,
8). The viscerocranium is metamerically organized in
register with cranial nerves and pharyngeal arches.
Prechordal neurocranium is the most anterior, premandibular component that belongs to the same segment as
the ophthalmic nerve. It was incorporated into the
neurocranium in association with the mouth formation
in ancestral vertebrates before the formation of the
masticatory jaw and utilized and modified to support
the brain through vertebrate evolution (Figs. 3, 8). A
number of events involved in the metamerical patterning of the viscerocranium are under the control of
genetic codes, with the Otx2 gene expressed anteriorly
and the Hox genes posteriorly (Fig. 8). A default state
exists in the posterior part of the first arch being
destined for middle ear structures, whose evolutionary
and embryological constraints imposed on the vertebrate body plan are of great interest. The anterior part
of the mandibular arch, on the other hand, is under
Otx2 control and destined to develop into the mandible.
Otx2 gene may have recruited a number of developmental cascades in the course of diversification of this
cartilage element. At the same time, this gene may
have been utilized in the masticatory system with
mesencephalic trigeminal neurons and midbrain crest
cells in transition from the agnatha to gnathostomata
(Matsuo et al., 1995).
In gnathostome history, modification of the mandibular arch skeleton was remarkable as shown by the
specification of the middle ear ossicles and of the
secondary cranial base in mammals. The default state
for Hox or Otx genes might have some relevance to the
apparently unique nature of this arch. Several non-Hox
homeobox genes such as gsc, Msx, and Dlx are expressed in a wide range of pharyngeal ectomesenchyme, but their unique functions in the mandibular
arch are suggested by disruptions of these genes in
mice. It is noteworthy that Hoxa-2 expression has been
suggested to restrict the function of gsc to the first arch
(Mallo and Gridley, 1996). The default state might thus
be the most specified state in patterning of the skeletogenic ectomesenchyme. The production of mice that
ectopically express Otx2 or Hoxa-2 gene in this region is
awaited.
MORPHOGENESIS OF THE MAMMALIAN SKULL
ACKNOWLEDGMENTS
We wish to thank Dr. Noriko Osumi-Yamashita and
Dr. Kazuhiro Eto for critical reading of the manuscript
and for providing us with unpublished data. Our work
cited was supported in part by grants-in-aid from the
Ministry of Education, Science and Culture of Japan
(Specially Promoted Research), and the Science and
Technology Agency of Japan.
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