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The Cells that Fill the Bill: Neural Crest and the Evolution of Craniofacial DevelopmentDepartment of Orthopaedic Surgery, University of California at San Francisco, 533 Parnassus Avenue, U-453, San Francisco, CA 94143-0514, USA Correspondence: * corresponding author, a.j.smith{at}bham.ac.uk
Avian embryos, which have been studied scientifically since Aristotle, continue to persevere as invaluable research tools, especially for our understanding of the development and evolution of the craniofacial skeleton. Whether the topic is beak shape in Darwin’s finches or signaling interactions that underlie bone and tooth formation, birds offer advantages for craniofacial biology that uniquely complement the strengths of other vertebrate model systems, such as fish, frogs, and mice. Several papers published during the past few years have helped pinpoint molecular and cellular mechanisms that pattern the face and jaws through experiments that could only have been done together with our feathered friends. Ultimately, such knowledge will be essential for devising novel clinical approaches to treat and/or prevent diseases, injuries, and birth defects that affect the human craniofacial skeleton. Here we review recent insights plucked from avians on key developmental processes that generate craniofacial diversity.
Key Words: neural crest cells • craniofacial • development • experimental embryology • chimeras • evolutionary biology
The development of the skeleton requires the precise orchestration of complex spatiotemporal signaling interactions among molecules, cells, and tissues. Nowhere is this complexity better demonstrated than in the head, where a great number of disparate parts come together to form a structurally intricate and functionally integrated skull. Thus, not surprisingly, congenital defects in craniofacial bones are relatively common, with individuals presenting overt phenotypes leading to distinct physical and social challenges. In fact, craniofacial mineralized tissue anomalies are involved in one-third of all congenital birth defects, which is approximately one in 300–600 live births (Gorlin et al., 1990). While existing treatments can be considered adequate, the potential exists to prevent or mitigate craniofacial skeletal anomalies entirely by means of novel molecular and stem-cell-based therapies. But achieving such clinical advancements will require substantial resources and more basic science data. Much of what is understood about the development of the craniofacial skeleton comes from more than a century of dedicated investigation of the cranial neural crest (Noden and Schneider, 2006). Neural crest cells arise from the margins of the neuro-epithelium, and they migrate laterally and ventrally to fill the facial prominences with mesenchyme. Alterations in neural crest cell migration and proliferation often lead to profound pathologies (Garg et al., 2001; Vitelli et al., 2002; Dixon et al., 2006; Jones et al., 2008). The neural-crest-derived mesenchyme eventually forms the facial and jaw skeletons (Noden and Trainor, 2005). Additionally, cranial neural crest cells contribute to the cranial ganglia, sympathetic nervous system, adrenal medulla (chromaffin cells), and melanocytes (Hall, 2005). In mammals, they also generate the dentin, dental pulp, alveolar bone, and periodontal ligament that are associated with teeth (Chai et al., 2000). Trunk neural crest cells do not differentiate into skeletal cells in vivo, although this capacity has been realized in vitro (McGonnell and Graham, 2002; Abzhanov et al., 2003). Neural crest cells have been considered to be stem cells, due to their ability to self-renew and differentiate into multiple fates (Crane and Trainor, 2006). Yet the extent to which they meet these criteria in vivo remains unresolved. In culture, neural-crest-like cells have been isolated from human embryonic stem cells and differentiated into Schwann cells, glial cells, peripheral neurons, melanocytes, pericytes, adipocytes, osteoblasts, and chondroblasts (Lee et al., 2007; Motohashi et al., 2007). These studies, along with the systematic mapping of human neural crest cell streams (O’Rahilly and Muller, 2007), provide valuable information on the biology of human neural crest cells, which will surely be a part of new clinical strategies for treating individuals with patterning defects in the craniofacial skeleton. However, for obvious reasons, there are severe limitations to what can be obtained about mechanisms that pattern human neural-crest-derived skeletal tissues in vivo. Therefore, a menagerie of animal models—including chick, quail, duck, quail-duck chimeras, Darwin’s finches, and mouse-chick chimeras—has become especially useful.
For several reasons, craniofacial osteogenesis can be considered dissimilar from the bone formation that occurs in the remainder of the skeleton (Helms and Schneider, 2003; Richman and Lee, 2003; Chung et al., 2004; Abzhanov et al., 2007; Wang et al., 2007). First, a majority of bones in the skull develops through intramembranous ossification, which involves the direct deposition of an osteoid matrix by mesenchyme. Other bones in the skull, as well as the post-cranial skeleton, form primarily via endochondral ossification, which is where bone replaces a cartilaginous template. Second, most skull bones are derived from neural crest cells, whereas the rest of the skeleton is of mesodermal origin. Third, craniofacial osteogenesis seems to involve molecular osteogenic pathways that are different from those required post-cranially. For example, mis-expression of hypoxia-inducible factor-  (HIF-) in transgenic mice has a profound effect on the axial and appendicular skeletons, but little or no effect on craniofacial bones (Wang et al., 2007). From a clinical perspective, these distinct mechanisms of bone formation may explain surgical observations of why calvarial or mandibular bone grafts (i.e., partially or fully derived from neural crest cells, respectively) incorporate better than iliac bone grafts (i.e., mesoderm-derived) in maxillary or alveolar bone augmentations (Hall, 2005; Crespi et al., 2007).
While many model organisms have been used to examine the role of neural crest cells during craniofacial development and evolution, much current knowledge has been collected through the use of several bird species. Chicken development has been studied for thousands of years, with the first documented observations attributed to Aristotle, who compared embryos that were incubated for various amounts of time (Kember, 1971). These initial endeavors not only demonstrate Aristotle’s prescience for the field of developmental biology, but also highlight embryo accessibility as a major strength of avian systems. Over two millennia later, Hamburger and Hamilton (1951) systematically categorized chick development into 46 stages based on morphological features. Remarkably, all bird embryos, whether precocial or altricial, can be roughly sorted into the same staging table created by Hamburger and Hamilton (HH), which allows for the direct comparison of all avian species regardless of their evolutionary divergence (Starck and Ricklefs, 1998). The use of non-chicken avians for the study of craniofacial development and specifically for the characterization of neural crest cells was pioneered by Le Douarin and her colleagues in the early 1970s (reviewed in Le Douarin, 2004). Such an approach has been readily adopted (Le Douarin, 1973; Le Lievre and Le Douarin, 1975; Noden, 1978, 1983, 1986; Couly and Le Douarin, 1990; Couly et al., 1992, 1993; Selleck and Bronner-Fraser, 1995; Kontges and Lumsden, 1996; Baker et al., 1997, 1999; Schneider et al., 1999, 2001; Olivera-Martinez et al., 2000; Cobos et al., 2001; Lwigale, 2001; Borue and Noden, 2004; Marcucio et al., 2005; Noden and Schneider, 2006; Schienda et al., 2006). The transplantation of quail neural crest cells into chicks with the critical ability to distinguish quail-donor cells from chick-host cells was a major achievement in the characterization of neural crest cells, particularly in studies of cell fate mapping (reviewed in Clarke and Tickle, 1999). From these tissue transplantation experiments, avian systems have smoothly transitioned into the genomics era. The first avian genome sequenced and assembled by the International Chicken Genome Sequencing Consortium (2004) was that of the Red Jungle Fowl (Gallus gallus), the ancestor of domestic chickens. Comparative mapping, which evaluates the location of homologous genes between species, suggests that organization of the human genome is more like that of the chicken than that of the mouse (Burt et al., 1999). This surprising result reminds us that the study of one animal model system may be insufficient for the application of results to humans, and that an inter-specific approach can be most informative. Currently, many molecular manipulation techniques are available for the mis-expression of genes in avian systems. These include the use of replication-competent avian sarcoma (RCAS) retroviruses (Hughes, 2004), electroporation (Itasaki et al., 1999; Krull, 2004; Nakamura et al., 2004), and siRNA and antisense oligonucleotides for gene repression (Kos et al., 2003; Rao et al., 2004). A fortuitous characteristic of RCAS vectors is their apparent inability to spread across basement membranes, thereby confining mis-expression of genes specifically to mesenchyme or epithelium (Abzhanov et al., 2004). Advances in laser-capture microdissection techniques also allow specific tissues to be isolated for genomic and proteomic analyses (Espina et al., 2007). One of the conspicuous limitations of avian systems has been the inability to generate transgenic animals. Several factors have hampered stable modification of the chicken genome (Sang, 2006). Not only are the eggs difficult to manipulate, due to the abundant yolk and size, but also, by the time a fertilized egg is laid, it has already advanced to a stage of ~ 60,000 cells. Lentiviral vector transduction of newly laid eggs and the isolation of chick embryonic stem cells for in vitro modification to generate chimeric chickens have met with limited or no success (McGrew et al., 2004; van de Lavoir et al., 2006b). Recently, van de Lavoir et al.(2006a) isolated and cultured primordial germ cells, the precursors of germ cells. The cultured cells were genetically modified by the incorporation of β-actin-eGFP and injected into the bloodstream of developing embryos, which were then incubated and hatched. Hatched males were crossed with wild-type hens. The genetically modified primordial germ cells maintained their commitment to the germ line, resulting in offspring derived from GFP-expressing transgenic primordial germ cells (van de Lavoir et al., 2006a). The next challenge is to demonstrate effective gene targeting in cultured primodial germ cells. However, the work by van de Lavoir et al.(2006a) is an exciting step toward the realization of transgenic chickens. Moreover, this method may be applied to yield high levels of therapeutic proteins that are glycosylated similarly to human proteins (Sang, 2006). Such advances in molecular and transgenic techniques will clearly enhance the experimental potential of avian systems.
Birds display magnificent variation in their beak morphology. Despite this diversity, all beaks originate from equivalent embryonic primordia, tissues, and cells. The upper beak forms from the frontonasal and paired maxillary primordia, whereas the lower beak arises from the mandibular primordia (Fig. 1  ). Each primordium is comprised primarily of two tissues, mesenchyme and epithelium. Cranial mesenchyme consists of loosely associated spindle-shaped cells derived from either the neural crest or the mesoderm. Epithelium functions as a sheet of connected cells that surrounds the mesenchyme and forms a barrier to the environment. Epithelia around the facial primordia arise from oral ectoderm and pharyngeal endoderm. Sandwiched between the epithelium and mesenchyme is a thin, acellular basement membrane derived from mesenchyme. This basement membrane plays a regulatory role in epithelial-mesenchymal signaling, and is characterized by the presence of collagen types III, IV and VII (Paulsson, 1992).
Several studies have demonstrated the distinct roles of epithelium and mesenchyme during beak patterning (Le Douarin et al., 2004; Helms et al., 2005; Schneider, 2005). Epithelia, through a mixture of secreted factors such as Shh and Fgf8, establish positional cues to align the upper beak (Hu and Helms, 1999; Schneider et al., 2001; Hu et al., 2003; Foppiano et al., 2007) and direct the outgrowth and orientation of skeletal elements (Shigetani et al., 2000; Abzhanov and Tabin, 2004). Similarly, epithelium derived from pharyngeal endoderm is necessary for the formation and arrangement of facial skeletal elements (Couly et al., 2002). Thus, epithelia seem to supply the positional cues and local maintenance factors required for pattern outgrowth by eliciting programmatic responses from underlying mesenchyme (Richman and Tickle, 1989; Schneider, 2005). Complementing these epithelial studies is work designed to understand the role of mesenchyme in patterning the beak. In particular, experiments have been performed in a variety of avians to identify and characterize the molecular and cellular mechanisms that generate species-specific differences. Such studies demonstrate the dominant role of mesenchyme and have identified molecular factors involved in the evolution of species-specific skeletal patterns.
Quail-Duck Chimeras
Transplanting from quail to duck those cranial neural crest cells destined to form the beak produced chimeric "quck" embryos (Schneider and Helms, 2003). Chimeric "duail" embryos were also made by transplanting duck neural crest cells into quail (Fig. 1
Subsequent work has expanded these conclusions to include cranial feather development, which is considered a classic system for understanding the functioning of epithelial-mesenchymal signaling interactions like those that underlie mammalian tooth formation (Eames and Schneider, 2005; Schneider, 2005). In the same way, tissue recombination and extirpation experiments with chicken and mouse embryos have long shown that interactions between mesenchyme and adjacent epithelium underlie the intramembranous ossification of the mandible. What has remained unclear are the precise roles for epithelium and mesenchyme, as well as the specific signaling pathways through which these tissues regulate bone formation. To identify signaling events that determine when bone forms, and to elucidate the function of mesenchyme and epithelium, investigators have again used quail-duck chimeras (Merrill et al., 2008). Pre-migratory cranial neural crest cells destined to form bone in the lower jaw were transplanted unilaterally from quail to duck. In resulting chimeras, quail donor mesenchyme established a significantly faster program for osteogenesis on both the molecular and histological levels, within the relatively slower duck host environment (Fig. 2
BMP/Calmodulin regulation and Darwin’s Finches To understand the basis for species-specific differences in beak morphology between chick and duck, investigators used short pulses of BrdU (5-bromo-2'-deoxyuridine) to analyze proliferative or growth zones in the frontonasal process (Wu et al., 2004, 2006). In both species, distinct, bilateral proliferative zones are present at stage HH26. Chick embryos at HH28 showed convergence of bilateral proliferative zones into one centrally localized zone, whereas in the duck, the bilaterally positioned proliferative zones persisted, widening the developing frontonasal process. Since BMPs and specifically BMP4 play a role in craniofacial osteogenesis (Francis-West et al., 1994; Ashique et al., 2002a,b; Merrill et al., 2008), the authors examined the expression level and profile of Bmp4 in the frontonasal process of both chick and duck. Bmp4 was found to be expressed at much higher levels in duck compared with chick throughout the neural-crest-derived mesenchyme. Moreover, the expression profile of Bmp4 was closely associated with the shifting proliferative zones. These observations suggest that BMP4 enhances proliferation in the growth zones, resulting in species-specific beak patterning. To test whether BMP4 drives beak growth, Bmp4 was over-expressed with RCAS retrovirus in the mesenchyme of the chick frontonasal process. This led to significant increases in size (i.e., width and depth) of the beaks compared with controls. Similar phenotypes were obtained with placement of BMP4-coated beads. Moreover, when Noggin, a BMP-antagonist, was expressed with RCAS retroviruses in the same region, beaks were miniaturized. The extent to which such molecular mechanisms operate in natural systems was addressed in a well-known group of birds from the Galápagos Islands. Upon his visit to the Galápagos Islands in 1835, Charles Darwin observed the adaptive radiation of 14 closely related species of birds from a single ancestral stock (Bowman, 1961). These birds, famously known as Darwin’s finches, are considered by many to be the ultimate demonstration of rapid morphological evolution in response to natural selection. Some state that, "Darwin’s finches are to evolutionary biology what Newton’s apple is to physics" (Pennisi, 2004). The evolution of the various species of finches has historically been attributed to natural selective pressures, such as environmental niches, competition for resources, or mating signals (Schneider, 2007). In particular, the beaks of the finches are the primary distinguishing features, which are selected for in accordance with the differences in their respective diets (Bowman, 1961). Thus, ground finches have deep and wide beaks for crushing seeds, whereas cactus finches have long and pointed beaks for reaching into cactus flowers and fruits. Abzhanov et al.(2004) compared and analyzed six species of Darwin’s finches in the genus Geospiza: G. difficilis (considered to be the most basal species), with a small symmetrical beak; 3 ground finches with broad, deep beaks (G. fuliginosa, G. fortis, and G. magnirostris); and 2 cactus finches with long, pointed beaks (G. scandens and G. conirostris). The expression patterns of a variety of growth factors were examined (i.e., Shh, Fgf8, Bmp2, Bmp4, Bmp7). The expression of Bmp4 showed a striking correlation with beak morphology. Thus, all 3 ground finches with deep, wide beaks (G. fuliginosa, G. fortis, and G. magnirostris) showed elevated levels of Bmp4 expression compared with the basal G. difficilis. As a functional test, Bmp4 was over-expressed in the mesenchyme of chick frontonasal process by means of an RCAS retrovirus, resulting in deep, broad beaks similar to those of ground finches. By utilizing a candidate gene approach, Abzhanov et al. (2004) and Wu et al.(2004) independently arrived at the same conclusion: that over-expression of Bmp4 in neural-crest-derived mesenchyme is sufficient to generate species-specific beak morphology.
Despite generating important information, the candidate approach failed to yield any novel factors that could be involved in the evolution of a longer beak morphology characteristic of cactus finches. Therefore, to identify molecular factors and pathways regulating beak length, Abzhanov et al.(2006) merged microarray technology with their previous work on Darwin’s finches. A custom DNA microarray was printed with RNA isolated from multiple frontonasal processes of G. fortis. Four species of Geospiza (2 ground finches - G. magnirostris, G. fortis; and 2 cactus finches - G. fuliginosa, G. scandens) were then directly compared against a common reference sample from G. difficilis (Fig. 3
Mouse-Chick Chimeras The combination of mouse and chick models in neural crest-transplantation experiments has generated interesting information regarding the role of neural-crest-derived mesenchyme in tooth development. The mouse-chick chimeric system was originally designed for the study of neurogenesis (Fontaine-Perus et al., 1997), but many soon realized that this system would serve as a useful model to study the development of teeth (Lwigale and Schneider, 2008). Birds are believed to have lost their teeth about 80 million years ago; however, several genes involved in tooth development continue to be expressed in the mandibular and maxillary primordia (Francis-West et al., 1998; Schneider et al., 1999). For example, the homeobox gene Pitx2, which is the earliest known marker of presumptive dental epithelium (Mucchielli et al., 1997), and the secreted factor Fgf8 are expressed in equivalent regions of chick epithelium at HH21 (approximately mouse E10.5) (Mitsiadis et al., 2003, 2006), whereas Bmp4 and Shh are not expressed in these domains. Tooth development is comprised of a complex cascade of reciprocal inductive and permissive interactions between epithelium and neural-crest-derived mesenchyme. Many of the signaling pathways regulating inductive tissue interactions have been elucidated by a range of approaches, including transgenic mice (Thesleff and Sharpe, 1997; Peters and Balling, 1999). From in vitro tissue recombination experiments, oral epithelium has been shown to provide the instructive signal that initiates tooth development (Mina and Kollar, 1987; Lumsden, 1988). Presumptive dental epithelium from embryonic days 9 to 11 (E9–E11) mice could initiate tooth formation in non-dental neural-crest-derived mesenchyme. Subsequently, reciprocal interaction of E12 neural crest mesenchyme instructs epithelium to form tooth-like structures. Thus, dental epithelium is generally considered to be the initiator of tooth formation, even though heterospecific in vitro tissue recombination experiments suggest mesenchyme to be the initiating tissue (Lemus, 1995). By grafting E8 mouse neural crest cells into stage-equivalent chick, Mitsiadis et al. (2003, 2006) demonstrated the successful incorporation of mouse neural crest cells into beak mesenchyme. More importantly, mouse-chick chimeras showed ingrowths of oral epithelium with tooth bud and cap configurations. There was no evidence of epithelium-derived enamel. Furthermore, mouse neural-crest-derived mesenchyme induced and/or maintained oral epithelial expression of Pitx2, Fgf8, Bmp4, and Shh (Mitsiadis et al., 2003, 2006). Grafted neural crest cells from the E8 mouse populate the upper beak (maxillary) and lower beak (mandibular) primordia, and interact with oral epithelium one day after neural crest transplantation. E9–E11 presumptive dental epithelium, which, with instructing mesenchyme, has been attributed to initiate tooth development in tissue recombination experiments (Mina and Kollar, 1987; Lumsden, 1988), appears to be pre-patterned by neural-crest-derived mesenchyme. Thus, mouse-chick chimeras indicate that neural-crest-derived mesenchyme possesses odontogenic potential to initiate tooth formation.
Craniofacial bones have been highly modified during evolution and, as a result, represent some of the most diversified and highly adapted anatomical structures in our bodies. Historically, much attention has been given to the role of external factors such as the environmental niche, competition for resources, or mating behavior in directing the course of craniofacial evolution, but recent studies are beginning to provide a deeper understanding of developmental mechanisms that may have facilitated the rapid diversification of the craniofacial complex (Schneider, 2005). Such developmental mechanisms are rooted deeply in the origins, abilities, and roles of the cranial neural crest cells that ultimately produce the facial and jaw skeletons. The unique properties of neural crest cells spawned the "New Head" hypothesis, to account for the evolution of vertebrates from passive filter feeders to active predators (Gans and Northcutt, 1983; Graham et al., 2004; Northcutt, 2005). At least three features in the developmental programs of craniofacial mineralized tissues potentially predispose them to rapid evolutionary transformations (Schneider, 2005). First, to reiterate, neural-crest-derived mesenchyme acts as the dominant source of species-specific patterning information. Thus, mesenchyme serves as a conductive target of natural selection and a driving force for generating phenotypic variation. Observations from quail-duck chimeras, the expression patterns in Darwin’s finches, over-expression of Bmp4 and CaMKII in chick facial mesenchyme, and mouse-chick chimeras suggest that genetic changes to mesenchyme alone during development may be sufficient to provide the material basis for evolution. Second, the program for osteogenesis operates as a module of tightly integrated molecular and histogenic events that are choreographed by the mesenchyme. This includes the series of epithelial– mesenchymal interactions underlying intramembranous ossification and the regulation of molecular pathways known to be essential to skeletal patterning and growth. By enabling developmental programs to be enacted in a variety of new contexts, modularity may be an essential element for enhancing the "evolvability" of anatomical structures. Third, developmental programs possess plasticity, a measure of the extent to which ontogenetic systems can respond to internal and external perturbations and produce an integrated and sustainable phenotype. As highlighted in quail-duck and mouse-chick chimeras, host tissues readily respond to donor neural crest mesenchyme and incorporate morphogenetic modifications (i.e., molecular and histogenic events) introduced by internal stimuli. Concomitantly, neural crest mesenchyme enacts its spatiotemporal programs, which results in the creation of a donor phenotype in the host. While natural selection can enable a particular phenotype to become seamlessly fitted to its environment, the means to attain this condition is adaptability, and adaptability occurs as a by-product of the amount of spatiotemporal plasticity built into a given developmental system. Changes in coding and non-coding DNA sequences, especially mutations in cis-regulatory elements, are the principal enabling events for natural selection and consequent morphological evolution (Stern, 2000; Wray, 2003; Carroll, 2005). Cis- regulatory mutations predominantly modify the timing, levels, and/or spatial domains of gene expression, which, in turn, affects morphology. For example, replacement of a mouse limb-specific enhancer of Prx1 with the orthologous bat sequence results in elevated levels of Prx1 expression in the developing mouse forelimb, and leads to longer forelimbs (Cretekos et al., 2008). In addition, quail-duck and mouse-chick chimera experiments—which are set apart from classic frog and salamander transplant studies because they incorporate molecular biology and analyses of underlying genetic cascades—demonstrate that much of the driving force for evolutionary change is coming from the mesenchyme via the regulation of its own gene expression as well as that in surrounding tissues (Mitsiadis et al., 2003, 2006; Schneider and Helms, 2003; Eames and Schneider, 2005, 2008; Merrill et al., 2008). In contrast, mutations within coding sequences of genes can also contribute to morphological modifications. For example, there is a strong correlation among the length of Runx2 glutamine-alanine (QA) tandem-repeats, Runx2 transcriptional activity, and facial length in domestic dogs (Sears et al., 2007). Mutations in coding sequence often lead to changes in DNA or protein interactions that affect the subsequent transcriptional or signaling properties of the gene product. However, if the gene product is expressed in multiple tissues, the coding sequence mutation is pleiotropic, and the gene locus contains multiple cis-regulatory elements (3 characteristics shared by most genes), then evolution is more likely to occur through changes in cis-regulatory sequences (Stern, 2000; Wray, 2003; Carroll, 2005; Cretekos et al., 2008). A challenge in future studies is to elucidate the precise molecular mechanisms that drive genetic changes governing facial morphology and, ultimately, the evolution of species.
Avian systems have been instrumental in deciphering the roles of epithelium and mesenchyme in the development and evolution of the craniofacial skeleton. Although epithelium and mesenchyme can each take on the function of inducer with respect to craniofacial patterning (Richman and Lee, 2003), numerous experiments point to neural-crest-derived mesenchyme as the dominant instructive tissue in the initiation of craniofacial bone and tooth formation. Epithelium is intimately involved and necessary for craniofacial patterning, but tends to plays a more permissive role, heeding instructions from mesenchyme. Clearly, much work is still needed to achieve a comprehensive understanding of how craniofacial bones and teeth develop and evolve. Many questions remain. For example, what factors regulate BMP4 and CaM/CaMKII signaling during beak morphogenesis? What are the neural-crest-derived molecular and cellular mechanisms involved in pre-patterning oral epithelium before mouse E9? Considering that CaM is a calcium-interacting/ sensing protein, does the amount of dietary calcium intake play a role in its regulation and subsequent effect on beak length? Last, if beak morphology can be altered and tooth formation can be initiated in birds, could this information be applied in humans to reconstruct and regenerate alveolar bones and ridges, or "awaken" tooth formation in edentulous individuals? What remains clear is that an intimate and equal partnership of basic research in avian and other model systems, along with applicable translational and clinical approaches, is currently the best method to improve therapies for the treatment of conditions that afflict the face and oral cavity.
A.H.J. would like to dedicate this publication to Dr. Jaroslav Sodek, who died suddenly in August, 2007. Many in the science community, particularly the young investigators who greatly benefited and those who would have benefited from his mentor-ship, will miss Jaro. We lost not only a great scientist but also a great person and friend. This work was supported by a fellowship from the Canadian Institutes of Health Research (CIHR) to A.H.J.; and by R01 DE016402-01 from the NIDCR, R21 AR052513-01 from the NIAMS, and Research Grant 5-FY04-26 from the March of Dimes Birth Defects Foundation to R.A.S.
A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. Received for publication April 18, 2008. Revision received July 10, 2008. Accepted for publication July 16, 2008.
Journal of Dental Research, Vol. 88, No. 1,
12-21 (2009)
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ABSTRACT
INTRODUCTION
