1 Department of Plastic and Reconstructive Surgery, Stanford University,
Stanford, CA 94305, USA
2 Department of Obstetrics and Gynecology, Montefiore Medical Center/Albert
Einstein, College of Medicine, Bronx, NY, USA
* Author for correspondence (e-mail: jhelms{at}stanford.edu)
SUMMARY
No region of our anatomy more powerfully conveys our emotions nor elicits more profound reactions when disease or genetic disorders disfigure it than the face. Recent progress has been made towards defining the tissue interactions and molecular mechanisms that control craniofacial morphogenesis. Some insights have come from genetic manipulations and others from tissue recombinations and biochemical approaches, which have revealed the molecular underpinnings of facial morphogenesis. Changes in craniofacial architecture also lie at the heart of evolutionary adaptation, as new studies in fish and fowl attest. Together, these findings reveal much about molecular and tissue interactions behind craniofacial development.
Introduction
For all intents and purposes, craniofacial development is initiated as soon
as the anteroposterior axis of an embryo is established. The ability to
specify a head structure, rather than reiterate another body segment, was a
crucial step in vertebrate evolution that corresponded to the acquisition of
two cell populations: the neural crest and the ectodermal placodes (reviewed
by Basch et al., 2004;
McCabe et al., 2004
). In
recent years, new data have begun to reveal how the neural crest cell
population is actually generated, what types of controls are in place to
modify neural crest cell migration and, ultimately, the role that this cell
population plays in establishing the pattern of the craniofacial skeleton.
Although the neural crest receives a significant amount of attention, it is
not the only craniofacial tissue with patterning information. New studies have
further clarified the contribution of epithelia as a source of patterning
information for the face. Regardless of whether epithelia are ectodermal in
origin [covering the facial prominences
(Hu et al., 2003)], or are
neural ectoderm (Cordero et al.,
2004
; Creuzet et al.,
2004
; Walshe and Mason,
2003
), or are of endodermal origin and line the pharynx
(Ruhin et al., 2003
), these
tissues can no longer be viewed as being bystanders in the process of
craniofacial morphogenesis. In a growing number of cases, epithelial tissues
are actually the instigator of morphological change. Our review focuses on
innovative studies that have addressed these issues, sometimes with new and
unexpected results. Several other reviews are also available that provide
excellent summaries of related work
(Francis-West et al., 2003
;
Le Douarin et al., 2004
;
Manzanares and Nieto,
2003
).
In the beginning
Although the postnatal vertebrate head exhibits an exceedingly intricate
and varied morphology, the craniofacial complex initially has a much more
simple geometry, consisting of a series of swellings or prominences that
undergo growth, fusion and expansion (Fig.
1). There are seven prominences that comprise the vertebrate face:
the midline frontonasal prominence and three paired structures derived from
the first pharyngeal (branchial) arch (Fig.
1). The frontonasal prominence contributes to the forehead, the
middle of the nose, the philtrum of the upper lip and the primary palate,
while the lateral nasal prominence forms the sides (ala) of the nose
(Larson, 2001)
(Fig. 1). Until recently, it
was thought that the ventral region of the first pharyngeal (branchial) arch
gave rise to the mandibular prominence and therefore the lower jaw, and that
the dorsal region of the first arch gave rise to the maxillary prominences,
which form the sides of the middle and lower face, the lateral borders of the
lips, and the secondary palate (Fig.
1). Two new studies, carried out in avians and axolotls, contest
this view and demonstrate that at least part of this fatemap is incorrect.
Using DiI labeling to track the fates of cells, both groups show that the
ventral region of the first arch actually gives rise to both maxillary and
mandibular skeletal elements, rather than to only the mandibular elements, as
previously thought (Cerny et al.,
2004
; Lee et al.,
2004
) (Fig. 1).
Which cell populations in the first arch actually contribute to a particular
skeletal element, however, is still not known. These new studies also indicate
the need for much more detailed fate maps of these latter stages of
craniofacial development; remarkably, this information is only now coming to
light after decades of study.
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One of the first crucial steps in craniofacial development occurs when head
ectoderm is subdivided into non-neural and neural regions, because this
effectively establishes which head epithelium will lie outside of the cranial
neural crest and which will lie inside it
(Fig. 2B-D). A subset of
epithelial cells located at this neural/non-neural boundary separate from the
epithelium, adopt a mesenchymal character and come between these two epithelia
as they start their migration (Fig.
2B-D). The epithelial-mesenchymal transition that marks the birth
date of the neural crest has been shown to depend upon cells shifting from G1
to S phase and, at least for trunk neural crest cells, this shift is dependent
upon bone morphogenetic protein (Bmp) signaling
(Burstyn-Cohen et al., 2004).
When Bmp signaling is inhibited by the overexpression of noggin, a Bmp
antagonist, the G1/S transition is blocked and neural crest cells are no
longer generated from the margins of the neural folds
(Burstyn-Cohen et al., 2004
).
Bmp signaling achieves this effect in part by regulating Wnt1
transcription (Burstyn-Cohen et al.,
2004
). In turn, Wnt signaling appears to be essential for the
generation of neural crest cells as inhibition of its activity can block the
production of neural crest cells
(Garcia-Castro et al.,
2002
).
In addition to Bmp and Wnt proteins, several new molecules have also been
implicated in the generation or early migration of neural crest cells. Sox
transcription factors, which are well known for their roles in skeletogenic
cell fate and sex determination, are also involved in generating neural crest
cells (Cheung and Briscoe,
2003; Honore et al.,
2003
; Perez-Alcala et al.,
2004
). These studies indicate that the overexpression of Sox genes
lengthens the developmental window during which cranial and trunk neural crest
cells can be induced, and then promotes neural crest-like characteristics in
those cells. Are these same molecular programs operating during the generation
of cranial neural crest cells? And is this molecular model of neural crest
induction species specific or can it be generalized to all vertebrates
(Streit and Stern, 1999
)?
Addressing the latter question is particularly relevant to craniofacial
biology because several craniofacial malformations, collectively referred to
as neurocristopathies, can be attributed to defects in the generation,
migration or survival of neural crest cells (reviewed by
Bolande, 1997
). If there is
species-specific variability in the model of neural crest generation, this
will have a profound impact on the interpretation of these neurocristopathic
anomalies.
Neural crest contributions to craniofacial patterning
Which tissue controls facial patterning? The answer to this question
continues to be debated, with strong data to support both sides of the
controversy. In two recent studies, the contribution of the neural crest to
facial patterning was assessed by swapping neural crest cells between ducks
and quails. It was found that switching frontonasal neural crest cells between
ducks and quails altered the countenances of the chimeras to such an extent
that ducks with quail frontonasal neural crest cells had a quail-like beak,
and quails carrying duck neural crest cells had a duck-like beak
(Schneider and Helms, 2003).
The molecular mechanisms underlying these facial transformations were hinted
at when transplanted neural crest cells were found to maintain their temporal
program of gene expression and to alter gene expression in the host epithelia
(Schneider and Helms, 2003
).
Tucker and Lumsden reached a near-identical conclusion when they independently
performed the same types of inter-species transplants
(Tucker and Lumsden, 2004
).
They, too, found that the capacity to form species-specific skeletal elements
in the head is an inherent property of the neural crest, and concluded that
this characteristic is produced in response to signals from epithelia
(Tucker and Lumsden, 2004
). In
fact, it appears as if the anteriormost neural crest cells acquire at least
some patterning information from epithelia, as discussed in the next section.
It should be emphasized that in both these studies, the extent to which facial
features were transformed was directly proportional to the number of
transplanted neural crest cells that made their way into the chimeric tissue.
In other words, the transformation was a `population-dependent' effect, as was
reported in much earlier transplantation studies
(Andres, 1949
). So it seems
that only when the contingency is large enough do neural crest cells follow
molecular cues that are generated and maintained by the assemblage itself,
disregarding signals emanating from the local environment. When the numbers of
transplanted cells are below some crucial threshold, then they appear to
respond to local cues from the surrounding epithelia. Just what these
population-dependent cues are, and how many cells are required to maintain
them, is unknown. What we do know, however, is that facial morphogenesis is
the cumulative result of reciprocal signaling between and among all of these
tissues, and that the issue of which tissue contains patterning information
becomes a question of timing. We discuss these ideas in subsequent
sections.
Epithelial contribution to craniofacial patterning
Oral ectoderm and tooth patterning
Perhaps no system better exemplifies the importance of reciprocal signaling
between epithelia and neural crest mesenchyme in the control of craniofacial
patterning than that of tooth development. The conflict over whether
mesenchyme or ectoderm was responsible for tooth morphology arose because of
two experimental results that, at first, appeared to be mutually exclusive
(Cobourne and Sharpe, 2003).
Recombinations of dental mesenchyme with non-dental ectoderm produce teeth,
implicating the mesenchyme as the source of dental patterning information
(Kollar and Baird, 1969
). But
recombinations of presumptive dental epithelium and naïve mesenchyme also
result in teeth, indicating that the epithelium controls dental patterning.
Which tissue contains the initial information for patterning
(Lumsden, 1988
; Mina and
Kollar, 1991; Miller, 1969
)
teeth? As it turns out, it depends on when you look. If early (embryonic day,
E10.5) chick oral ectoderm is used in the recombination experiments, then this
tissue directs patterning. However, if the experiment is conducted with E11.0
mesenchyme (after patterning information has been transferred to the
mesenchyme), then this tissue controls patterning (reviewed by
Miletich and Sharpe, 2003
).
This type of reciprocal signaling was demonstrated by transplanting cranial
neural crest cells from a mouse (which develops teeth) into a bird (which does
not), and resulted in the formation of tooth-like rudiments. Although the
experiment was first performed over 30 years ago
(Kollar and Fisher, 1980
),
investigators can now demonstrate that these teeth are composed of avian
epithelium and murine mesenchyme
(Mitsiadis et al., 2003
).
Therefore, despite the fact that birds have been edentulous (i.e. toothless)
for nearly 100 million years, avian oral ectoderm has apparently retained its
ability to induce tooth formation, provided the neural crest mesenchyme has
retained its capacity to respond. The molecular mediators of this patterning
information have also been identified. The general consensus in this field is
that future oral ectoderm is somehow imbued with a basic `pre-pattern' through
the nested expression of fibroblast growth factors (Fgfs), sonic hedgehog
(Shh) and Bmp4. These signals are then interpreted and refined by the
underlying mesenchyme into spatially restricted domains of homeobox gene
expression. In turn, these transcription factors regulate other signaling
molecules (Bmp, Wnt and Fgf proteins) that induce the epithelial folding and
invagination that signal the initiation of tooth development. Just how does
the future oral ectoderm acquire this basic pre-pattern? By extending previous
fate maps (Couly and Le Douarin,
1990
), Sharpe and colleagues show that the regionalization of the
oral ectoderm into Fgf8-positive (molar) and Fgf8-negative
(incisor) domains occurs long before the pharyngeal arches have formed; the
regionalization is evident as early as neurulation
(Haworth et al., 2004
). And
what regionalizes the ectoderm? The instigator of this patterning appears to
be pharyngeal endoderm (Haworth et al.,
2004
). This tissue does far more than set up a framework for tooth
development, however, as will become evident in the next section.
Pharyngeal endoderm and arch patterning
Experiments from Le Douarin and colleagues, and Graham and co-workers
demonstrate that the pharyngeal endoderm has a profound influence on the
morphogenesis of the middle and lower face
(Crump et al., 2004a;
Crump et al., 2004b
;
Trokovic et al., 2003
;
Veitch et al., 1999
). Recent
work shows that Fgf signaling is an essential component of this tissue
patterning. Kimmel and his colleagues used time-lapse microscopy in zebrafish
to demonstrate that pharyngeal pouches form when clusters of endoderm cells
migrate laterally, and that if Fgf8 is inactivated and Fgf3 is
knocked down with morpholinos, the migration of these endodermal cells is
disrupted (Crump et al.,
2004a
). Consequently, the pharyngeal pouches fail to form and the
pharyngeal arch cartilages are disorganized
(Crump et al., 2004a
). Not all
cartilages are equally affected, however; mandibular cartilages derived from
Hox-negative neural crest cells are less affected than are Hox-positive second
arch cells, a finding that has also been shown in avian embryos. In these
avian studies, pharyngeal endodermal grafts were positioned adjacent to the
neural tube (Ruhin et al.,
2003
). The response was a remarkable duplication in pharyngeal
arch skeletal structures, the general morphology of which correlated with the
level from which the endodermal graft was derived. Le Douarin and co-workers
also showed that removing the endoderm completely blocked the formation of the
pharyngeal arch skeleton. As in the zebrafish studies, they suggest that Fgf8
is a key mediator of this activity (Ruhin
et al., 2003
). Does the pharyngeal endoderm influence the
morphogenesis of the entire facial skeleton
(Ruhin et al., 2003
)? Analyses
of the zebrafish mutant, casanova, indicate not, because in this
animal the pharyngeal endoderm is not required for normal development of the
middle and upper part of the face (Aoki, 2002). Instead, two other epithelia,
the anterior (or forebrain) neuroectoderm and the facial/stomodeal ectoderm,
appear to have taken over this crucial role.
Neural and surface ectoderm: patterning the middle and upper face
When regions of facial ectoderm are transplanted to ectopic sites in the
avian face, the developmental fate of underlying frontonasal neural crest
cells is altered and the result is a duplication of upper beak structures
(Hu et al., 2003). This same
bit of facial ectoderm can elicit similar duplications when transplanted into
the first, Hox-negative, arch, but has no effect when transplanted into the
second, Hox-positive, arch (Hu et al.,
2003
). This result indirectly illustrates how neural crest
plasticity is balanced against a `pre-pattern', owing in no small part to the
expression of Hox genes in the facial tissues
(Creuzet et al., 2002
). What
types of signals imbue this facial ectoderm with the ability to re-specify the
fates of neural crest cells? Both Shh and Fgf8 are expressed
in juxtaposed nonoverlapping domains in this region of tissue, but whether
they are the molecules responsible for achieving this effect, or simply
molecular markers of an important boundary domain in the face, remains to be
determined.
Neural ectoderm is also a source of patterning information for the middle
and upper face, as has recently been shown in a series of experiments
conducted in zebrafish. In these experiments, Eberhart and Kimmel found that
Shh emanating from anterior ventral neuroectoderm directly patterned the
ventral surface ectoderm, without requiring an intermediate signal generated
by neural crest sandwiched between these two epithelia (J. Eberhart and C.
Kimmel, unpublished). The loss of neuroectodermal Shh prevented neural crest
cells from aggregating into condensations and eventually from forming skeletal
elements. This result supports previous findings in mice
(Jeong et al., 2004) and birds
(Cordero et al., 2004
).
Molecular mediators of craniofacial morphogenesis
Sometimes, the mechanisms that regulate normal development are best appreciated by studying cases of abnormal development. Human craniofacial malformations have been avidly catalogued since the Aristotelian era but only lately have researchers pinpointed some of the genes responsible. The next hurdle is to understand the function of the encoded proteins in craniofacial morphogenesis. This aim is complicated by the fact that these genes are invariably expressed in multiple tissues and at multiple times during facial development, and so separating their numerous functions becomes a difficult task. The case of holoprosencephaly illustrates this point perfectly.
A sonic boom
One of the best studied craniofacial abnormalities is holoprosencephaly
(HPE), a syndrome that is associated with perturbations in a handful of
Shh-related genes (Belloni et al.,
1996; Brown et al.,
1998
; Cole and Krauss,
2003
; Cordero et al., 2004a;
Gripp et al., 2000
;
Marini et al., 2003
;
Ming et al., 2002
;
Roessler et al., 1996
;
Roessler et al., 2003
). At one
end of the HPE spectrum, fetuses exhibit cyclopia, a condition characterized
by a single, central eye and no discernable nose, but a relatively
normal-looking middle and lower face
(Chiang et al., 2001
). At the
other extreme, obligate HPE carriers can have a normal facial appearance
(McKusick, 2000
). In an effort
to explain this remarkable phenotypic variation, Traiffort and colleagues
recently examined how specific human HPE mutations affected the structure and
function of the SHH protein. By coupling three-dimensional modeling of
fragments of the SHH protein with a series of functional assays, the
researchers found that most HPE mutations fall into one of three classes:
mutations that influenced zinc binding of the protein; those that affect the
auto-processing of SHH; and those that adversely alter SHH stability
(Traiffort et al., 2004
).
However, none of these mutation types could be linked to a specific phenotype
(Traiffort et al., 2004
),
confirming previous speculations along the same lines
(Dipple and McCabe, 2000
).
If there is no clear genotype-phenotype correlation, then what explains the
variable expressivity of this craniofacial malformation? One appealing
hypothesis is that environmental agents act in conjunction with an autosomal
dominant mutation to compromise Shh signaling
(Cordero et al., 2004;
Edison and Muenke, 2003
). If
this scenario were true, then varying the time in which an embryo was exposed
to an environmental teratogen could elicit different disease phenotypes. We
tested this hypothesis by exposing avian embryos to cyclopamine, a potent
inhibitor of the Hedgehog signaling pathway
(Chen et al., 2002a
;
Chen et al., 2002b
), and found
that by varying the delivery time so that it coincided with Shh
induction in the forebrain and later in the face, we could reproduce the
spectrum of HPE phenotypes (Cordero et
al., 2004
). Although this is unlikely to be the sole, or even the
predominant, explanation for variations in HPE phenotype, experiments such as
these indicate that Shh has a variety of functions in facial development. This
point is well illustrated by studies showing that Shh initially plays
a role in patterning the neural plate midline
(Chiang et al., 1996
), and
later is critically required for the proper development of a subset of neural
crest-derived facial bones (Hu and Helms,
1999
; Jeong et al.,
2004
). These data also imply that some, but not all, cranial
neural crest cells need a Hedgehog signal both to survive and, ultimately, to
differentiate appropriately (Ahlgren and
Bronner-Fraser, 1999
; Ahlgren
et al., 2002
).
Fgfs and craniofacial patterning: a question of timing
Even when the source of a signal important for craniofacial development has
been identified, there are often multiple sources of a particular morphogen,
and each source may control a different aspect of patterned outgrowth and cell
differentiation. This has been well illustrated in recent studies evaluating
the consequences of Fgf perturbation at four separate points in craniofacial
development. Early in craniofacial development, Fgf signaling is involved in
the production of dopaminergic neurons (Ye
et al., 1998); the same signal is crucial in establishing the
midbrain-hindbrain boundary (Scholpp et
al., 2003
). Later in development, Fgf signaling from ventral
forebrain and pharyngeal endoderm is required for pharyngeal skeletogenesis,
as inhibiting this pathway prevents the formation of the second arch skeleton
(Creuzet et al., 2004
;
Walshe and Mason, 2003
). Later
still, blocking Fgf signaling from the surface ectoderm disrupts outgrowth of
the frontonasal skeleton (A. Abzhanov, D. Hu, J. Sen, C. J. Tabin and J.A.H.,
unpublished). Finally, just before birth, disruptions in Fgf signaling cause
premature osteogenesis in the sutures
(Moore et al., 2002
;
Sarkar et al., 2001
). Clearly
then, Fgfs play multiple, fundamental roles in craniofacial morphogenesis, but
unraveling this complicated molecular machinery will have to await better
genetic and molecular tools that permit a more precise regulation of gene
activity.
Bmp proteins and craniofacial patterning in birds
Vertebrates exhibit a marvelous range of craniofacial features that are
designed to fit specialized niches and behaviors. These postnatal facial
features are immediately obvious, but during the embryonic period, vertebrate
faces look remarkably similar (Haeckel,
1897). The proteins that establish this basic blueprint of the
craniofacial region are still unidentified but likely candidates are those
same molecules that establish other developmental axes in vertebrates and
invertebrates: Hedgehog and Wnt proteins, and members of the Bmp and Fgf
families. Some new studies have begun to explore how different species use
these pathways to create distinctive facial features.
In the Galapagos finches, Darwin had noted that `a nearly perfect gradation
may be traced from a beak extraordinarily thick to one so fine that it may be
compared with that of a warbler.' (Darwin,
1859). We now know that these species-specific morphological
variations are evident during embryogenesis, and are first evident around
Hamburger and Hamilton (Hamburger and
Hamilton, 1951
) stage 22 (S. Brugmann and J.A.H., unpublished).
Prior to that time, the faces of different avian species are indistinguishable
from one another (Schneider and Helms,
2003
). Tabin and co-workers set out to understand how such
morphological variations might arise. They evaluated two finch species - the
ground and cactus finches - that represent the extremes in Galapagos finch
beak morphology (Grant, 1986
)
(Fig. 4A,F). At the time when
ground and cactus finch embryos appear similar, in situ hybridization analyses
by these investigators revealed a difference in the patterns of Bmp4
expression (Abzhanov et al.,
2004
) (see Fig. 4).
To test experimentally whether spatial and temporal changes in Bmp4
expression could account for the relative size and shape differences in these
finches' beaks, the investigators mis-expressed Bmp4 throughout the
mesenchyme of a chick frontonasal prominence
(Fig. 4D). This misexpression
converted the narrow short chick beak into a much broader bigger beak that
resembled that of the large ground finch
(Abzhanov et al., 2004
)
(Fig. 4D).
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These two studies indicate that modulations in Bmp4 activity can alter beak morphology, but they do not clarify whether Bmp4 is instigating these morphological changes or whether Bmp4 is being altered in response to another molecule. Nonetheless, as studies in fish show (as discussed below), Bmp4 has also been implicated in patterning the craniofacial complex in other organisms.
Bmp4 and craniofacial patterning in fish
Cichlids are small fish found in the rivers and lakes of the East African
rift valley that exhibit a dramatic variation in facial form, not unlike that
of finches (Fig. 5). An
astonishing 200 species are estimated to have evolved within the past 10
million years (Kocher, 2004),
which certainly places cichlids on the fast track in terms of evolutionary
diversity. This rapid diversification offers another advantage: as speciation
occurred relatively recently, interbreeding is possible. This means that two
species with dramatically different facial skeletons can be mated to generate
progeny with intermediate phenotypes, and in a recent series of experiments,
investigators did just that. Albertson and colleagues used the detailed
description of cichlid skeletons as a starting point
(Barel, 1983
) for a series of
morphometric analyses on two species of cichlids and their progeny (see
Fig. 5). The authors then
mapped genomic regions (so called quantitative trait loci - QTL) that
cosegregated with specific morphological alterations to the jaw skeleton.
Their findings showed that only a handful of QTL need to be modified to
provide a cichlid with a unique set of jaws
(Albertson et al., 2003a
;
Albertson et al., 2003b
) (see
also Box 1).
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Okada and co-workers focused on Bmp4 as a candidate gene that
might underlie one of these QTL (Terai et
al., 2002). They took advantage of the fact that the cichlids that
occupy the East African Great Lake exhibit a higher degree of speciation
relative to cichlids occupying the nearby rivers. Okada postulated that the
more highly speciated of the lake cichlids would exhibit an elevated frequency
of amino acid substitutions in those genes that were involved with generating
morphological variations. No significant differences in amino acid
substitution rates were observed for Otx1, Otx2 and Pax9. The pro-domain of
Bmp4, however, showed significant modifications
(Terai et al., 2002
). These
findings imply that post-translational modifications of Bmp4 could account for
at least some of the variations in the facial features of this fish, just as
it can in birds. However, it is once again not clear whether Bmp4 is
responding to, or is actually instigating, morphological change.
Evolution and patterning of the jaw
Faces have changed drastically throughout evolution and although differences in the length, width and breadth of facial features are certainly of great consequence, the most notable alteration has been the evolution of a hinged jaw. This advancement endowed its new owner with the ability to diversify its eating habits, thereby proffering a hefty leg up on the competition. Current studies in lampreys and fish are shedding new light on the molecular changes required for leaping this evolutionary hurdle.
In the portrait gallery of comparative anatomy, the larval form of jawless lampreys bear a remarkable resemblance to jawed animals, in that both possess a braincase and pharyngeal arches, which are the building blocks for much of the craniofacial skeleton. The question is, if jaw-lacking (agnathan) larvae and jaw-possessing (gnathostome) larvae have comparative facial features, then how did one species develop a hinged jaw while the other did not? Recent studies of Hox gene expression patterns may reveal the molecular mechanisms behind this transformation.
Hox genes are expressed in a nested pattern along the body axis, which has
led to the speculation that they provide cells with a regional identity. A
variety of functional tests, most recently by Wellik and Capecchi, have
provided convincing evidence to that effect in mice
(Wellik and Capecchi,
2003).
Gain- and loss-of-function studies in chicks have also demonstrated that
Hoxa2 gene expression constrains the range of decisions that cranial
neural crest cells can make as they differentiate into the facial skeleton
(Couly et al., 2002;
Hu et al., 2003
;
Ruhin et al., 2003
). In light
of these data, Cohn asked whether the loss of anterior Hox expression
correlated with the acquisition of a hinged jaw apparatus, because if
first-arch neural crest cells are Hox positive in a more primitive condition
but become Hox negative through evolution then, theoretically, these cells
would be at liberty to respond to new signals in their changing environment.
Such a newly acquired flexibility might then allow for adaptive variations in
the jaw structures formed by these neural crest cells.
Cohn examined jawless lamprey larvae and found that HoxL6 was
expressed in the first pharyngeal arch, which is a Hox-negative region in
jawed embryos (Cohn, 2002)
(see Fig. 6). Was this simply
an odd twist of fate for lampreys, as opposed to being a molecular feature of
a more primitive evolutionary condition? Lampreys are currently the only
agnathan available for study, so Cohn turned to a more primitive animal - the
cephalochordate Amphioxus, which also possesses a Hox cluster
(Ferrier et al., 2000
) - to
support his argument. As he had found with lampreys, the Hox homolog
AmphiHox6 was also expressed in the anterior head
(Cohn, 2002
) (see
Fig. 6), lending further
support to his hypothesis that loss of Hox gene expression correlates with the
gain of a hinged jaw joint.
|
Conclusions
A recent meeting organized by the Anatomical Society of Great Britain and Ireland demonstrated that the field of craniofacial biology attracts scientists from a wide range of disciplines. Developmental and evolutionary biologists, reproductive toxicologists, bioengineers and genome biologists have recently contributed to our understanding of the mechanisms by which the craniofacial tissues are patterned and their outgrowth regulated. We are tackling issues first posed by Darwin and reiterated by Spemann, Wolpert and other notable scientists, as they relate to the patterning of the craniofacial complex. There remain a number of pressing issues. For example, studies conducted in a single species are oftentimes presumed to represent conserved mechanisms of patterning across all species; although this approach has some utility, there are bound to be errors made as a result of over simplification. Generalizations from one species to another may cloud subtle variations that could be responsible for certain aspects of species-specific facial morphology. And although there is much to be learned about studying conserved molecular pathways and their various functions in craniofacial development, there are no studies to date that have addressed how these same morphogens create a face and not a limb bud or other structure. Finally, although the issue of whether the neural crest or epithelium contains patterning information might be settled (they both do), how the patterning process itself is instigated remains unknown. The next few years will undoubtedly yield resolution of these issues and invariably give rise to many more.
ACKNOWLEDGMENTS
Photographs and illustrations were kindly provided by the following individuals: J. E. Randall (labridae); P. Wainwright and the Linnean Society (labrid jaw diagrams); J. Dion and F. Hagblom (cichlids); C. Albertson and the National Academy of Sciences (cichlid jaw diagrams); and P. Grant (finches). We also thank C. Tabin, C.-M. Chuong, and Science for allowing us to reproduce figure panels. The authors also thank T. Schilling, P. Sharpe, S. Brugmann, S. Kuratani, J. Hanken and P. Herandez for helpful discussions regarding the manuscript, J. Eberhart and C. Kimmel for sharing data prior to publication, and C. Moreau for assistance with manuscript preparation. J.A.H. is supported, in part, by The Oak Foundation.
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