Embriologia Articulo

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New Insights in Facial DevelopmentGeoffrey H. Sperber

The recent sequencing of the human genome is revealing the template of

the directional signals and morphogenetic elements guiding development ofthe embryo. Of the estimated 25,000 genes of the human genome, some17,000 genes have been identified in contributing to craniofacial develop-ment. The complexities of the phenomena of cellular differentiation, histo-

genesis, tissue migration, apoptosis, melding and fusion of folds, and prom-inences in creating the human face are being elucidated by identifyinggenes, transcription factors, and signaling pathways that are responsible forthe phenotypic expression of facial development. Dysmorphology will po-tentially be anticipated and possibly biomimetically controlled by geneticand growth factor intervention rather than by post hoc treatment by me-chanical means. (Semin Orthod 2006;12:4-10.) 2006 Elsevier Inc. All rightsreserved.

. . .and each hurries toward its goal: although each isnot yet independent enough to indicate what it truly is;it still needs the help of its sister travelers and, therefore,although already designated for different ends, all three(germ layers) influence each other collectively untileach has reached an appropriate level.1

The enormous technological advances ingene identification, electron, scanning, trans-mission, fluorescence microscopy, and confocal

laser microscopy, immunohistochemistry, roent-gencephalometry, ultrasonography, computedtomographic (CT) scanning, nuclear magneticresonance imaging (MRI), 3D computer stereol-ogy, polymerase chain reaction (PCR) technol-ogy, and experimental cloning have revolu-tionized our capabilities for investigatingdevelopmental phenomena.

The current explosion of genetic informationemanating from the sequencing of the human

genome2 is providing insights into the basis ofthe mechanisms of embryogenesis. Of the esti-mated 25,000 genes in the human genome,some 17,000 genes have been identified in con-tributing to craniofacial development. Databasesof human genes have now become available thatcontain information to more than 21,000 genespooled from six collections of human comple-mentary DNAs.3 The advent of high-throughput

sequence analysis, functional genomic, metabo-lomic, transcriptomic, and bioinformatic tech-nologies has ushered in the postgenomic era.Ascribing specific functions to these genes is stilla daunting challenge, but it is the realization ofthe biology encoded within each gene that willprovide insights into developmental phenom-ena and their aberrations.

The concomitant coalescence of the currentcogent cornucopia of cognitive capabilities cre-ated by cascades of chemicals, cytokines, com-puters, and clinical conceptualizations of cepha-

logenesis is providing information on themorphogenetic mechanisms of facial fabrica-tion.

The initial differentiation of the three pri-mary germ layers provides the anlage for thesubsequent development of secondary and ter-tiary tissues and organs. The revelations of thecompleted sequencing of the human genome4

will enable identification of specific genes rele-vant to facial morphogenesis. The gene and pro-

From the Orthodontic Graduate Program, Department of Den-tistry, Faculty of Medicine and Dentistry, University of Alberta,Edmonton, Alberta, Canada.

Illustrations by Heather Spears, www.heatherspears.comAddress correspondence to G.H. Sperber, BSc Hons, BDS, MSc,

PhD, FICD, Dr Med Dent (hc), Orthodontic Graduate Program,Department of Dentistry, Faculty of Medicine and Dentistry, Uni-versity of Alberta, Edmonton, AB T6G 2N8, Canada. Phone: 780-492-5194; Fax: 780-492-1624;E-mail: [email protected]

2006 Elsevier Inc. All rights reserved.1073-8746/2000/1201-0$30.00/0doi:10.1053/j.sodo.2005.10.003

4 Seminars in Orthodontics, Vol 12, No 1 (March), 2006: pp 4-10


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tein expression patterns and tracking of migrat-ing tissues has become possible by opticalsectioning microscopy.5 The conundrum of thecomplicated choreography of the chromosomesand their contained genome in directing devel-

opment is still being elucidated. There are genesthat initiate the primary germ layers of ecto-derm, mesoderm, and endoderm, followed byneural plate folding and subdivision into theprosencephalon (forebrain), mesencephalon(midbrain), rhombencephalon (hindbrain),and spinal cord. Development of the face de-pends not only on the underlying brain and itssubdivisions of prosencephalon, mesencepha-lon, and rhombencephalon, but also on the ad-jacent secondary neural crest tissue arising fromthe dorsal margins of the neural folds at a veryearly stage of embryogenesis.6

Fundamental to facial formation is the differ-entiation, development, and migration of thesecondary germ layer tissue designated neuralcrest ectomesenchyme. This transitory pluripo-tential tissue arises from the lateral marginalcrests of the neural primordium and undergoesan epithelio-mesenchymal transition. The fate ofthe neural crest mesenchymal precursors intodifferentiated facial tissues is strongly restrictedby homeobox (HOX) gene expression. Facialmorphogenesis is controlled by multistep inter-actions between the ecto- and endodermal epi-

thelia and neural crest cells.6The differentiated oral epithelium becomes

regionalized early in development by the expres-sion of signaling molecules such as bone mor-phogenetic protein 4 (Bmp4) and fibroblastgrowth factor 8 (Ffg8). The initial ecto-endoder-mal regionalized spatial expression is later re-flected in the underlying mesenchyme differen-tiating into connective tissue, cartilage, bone,and teeth.7,8

Facial Development

The human face contains a remarkable topolog-ical complexity of organs and systems devoted tothe special senses of sight, sound, olfaction, andgustation, besides the general sensations oftouch, temperature, and pain perception. Thedevelopment of the stomatognathic apparatusfrom the archetypal oropharynx reflects a longphylogenetic evolutionary history9,10 that is con-densed into a brief period of ontogenesis.

The complex combination of the primarygerm layers and the subsequent differentiationof their derived tissues are dependent on postu-lated organizing centers related to the prosen-cephalon and rhombencephalon (Fig 1). These

organizing centers control developmentalfields that correspond with homeobox (HOX)genes that establish spatial identity of prospec-tive craniofacial compartments.11 The segmen-tation of the rhombencephalon into eight rhom-bomeres, under the direction of HOX genes, iscentral to the subsequent development of neuralcrest mesenchyme.12 The HOX genes are ex-pressed in a stepwise manner, delineating thecascading streams of ectomesenchyme that mi-grate from their dorsal origin to their ventraldestination to create six pharyngeal arches andfive facial prominencesthe median frontona-sal prominence and the paired maxillary andmandibular prominences, bordering the centraldepression of the stomodeum, the forerunner ofthe mouth (Fig 2). The frontonasal prominencesubsequently elevates into the bilateral medialand lateral nasal prominences surrounding thedepressions of the nasal pits that demarcate thefuture nostrils. Later, bilateral swellings arise ros-trally as the maxillary prominences (Fig 3).13

These facial swellings are the consequence ofneural crest ectomesenchyme invading the ros-troventral aspect of the prosencephalon. Out-

growth of the facial primordia is dependent onepithelial-mesenchymal interactions, with in-structive signals emanating from each other.Five key secreted growth factors control facialgrowth by regulation of cell proliferation, sur-vival, and apoptosis. These factors include endo-

Figure 1. Schematic depiction of postulated prosen-cephalic and rhombencephalic organizing centers.

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thelins, fibroblast growth factors (FGFs), sonic

hedgehog (SHH), wingless (Wnts), and bonemorphogenetic proteins (BMPs). These factorsinteract coordinately and interdependently toregulate growth and patterning of the develop-ing face.14,15 The complexity of contributions ofthe hundreds of genes to facial formation isbeing elucidated by identifying each genes in-dividual responsibility for each stage of develop-ment. The ever-constant new identification ofgene expression profiles of embryonic craniofa-

cial and oral structures has led to the develop-

ment of a consortium titled COGENE (Cranio-facial and Oral Gene Expression Network) thatcan be accessed online at http://hg.wustl.edu/COGENE/. Herein is contained a list of all iden-tified genes, growth factors, and signals involvedin the expression profiles of structures betweenthe 4th and 8.5 weeks of development. It is in themutation or deletion of genes, or the misappro-priation of growth factors and signals, that thecause of some of the defects of development is

Figure 2. Schematic depiction of gene expression patterns in the neural crest ectomesenchyme streamsmigrating into the facial and pharyngeal regions. Lateral perspective. R1 to 8: Rhombomeres in hindbrain.

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Figure 3. Frontal facial development depicting the relative contributions of the facial primordia. (A) Fourweeks: 64 genes upregulated. (B) Five weeks: 26 genes upregulated. (C) Six weeks: 36 genes upregulated in themedial nasal prominence; 45 genes upregulated in the lateral nasal prominence.

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revealed. The intricacies of RNA editing, com-plex regulatory networks, and crisscrossing mo-lecular pathways, together with the overlappingand redundancies of genetic expression pat-terns, make the unraveling of the skein of their

influences particularly difficult. Adding to theintrigue of gene expression profiles are the rev-elations of evolutionary adaptations in the newlyemerging field of evo-devo, wherein alteredregulatory patterning of genes accounts for phe-notypic changes that provide the basis for phy-logenetic changes.16,17

New genetic lineage markers are identifyingthe expression changes occurring in discretecomponents of the early embryonic face at dif-ferent stages. Thus, some 173 genes are ex-pressed in the frontonasal prominence, amongwhich are TBX10, TBX21, BARX1, BAPX1,EMX2, SOX10, MNT, ID1, and BRPF1, locatedon different chromosomes.

During the 4th week, 64 genes, including ho-meobox D9, zinc finger 197, transcription factor3, and homeobox D1 genes are upregulated.During the 5th week, a further 26 genes areupregulated in the frontonasal prominence.The medial nasal prominence exhibits 36 up-regulated genes in the 6th week, while the lat-eral nasal prominence expresses 45 genes in thesame period.18

The merging and fusion of the initially dis-

tinct facial primordia is dependent on neuralcrest migration and proliferation, epithelial-mes-enchymal transformations, and selective apopto-sis. Delayed or inadequate neural crest migra-tion, proliferation, or differentiation is thesource of numerous craniofacial neurocristopa-thy syndromes. Clefting is the result of the dis-tinct primordia failing to merge or fuse, and mayoccur between any of the primordia.

Skeletal Development

The craniofacial skeleton is composed of a com-plex assortment of neural crest and mesoderm-derived cartilages and bones highly modifiedduring evolution.19,20 Pharyngeal endoderm isan essential precursor of pharyngeal cartilagedevelopment. The endoderm of the first pharyn-geal pouch promotes region-specific cartilagedevelopment that regulates the local compac-tion and survival of skeletogenic neural crestcells.21 The subsequent development of the fa-

cial skeleton is patterned by a series of hierar-chical tissue interactions that designate the fa-cial bones. Ossification of the facial primordiacommences in the 8th week post conception byepithelial signals inducing membrane bones in

the maxillary and mandibular arches.22

Bilateral primary centers of intramembra-nous ossification appear for each of the viscero-cranial bones, commencing with the mandible,followed by the maxilla, frontal, parietal, squa-mous temporal, zygomatic, vomer, nasal, andlacrimal bones. Secondary ossification centersappear at variable ages in the maxilla at thezygomatic, orbitonasal, and nasopalatine sites(Fig 4).

The Mandible

The template for the mandible is laid down byMeckels cartilage of the first pharyngeal arch.Initial intramembranous ossification occurs at 6weeks post conception, the earliest of bones toossify. The primary ossification center is locatedat the site of bifurcation of the inferior alveolarnerve into the incisive and mental nerves (Fig 5)and spreads anteroposteriorly on the lateral as-pect of Meckels cartilage to encompass the car-tilage, which later disintegrates.

Secondary cartilages develop at the sites ofthe coronoid and condylar processes, and at the

angle, and together with the ventral-most tip ofMeckels cartilage, ossify endochondrally to con-join with the membrane bone of the body of themandible.23 Growth of the mandible dependson various functional matrices (muscles and ex-panding organs) acting on its different compo-

Figure 4. Intramembranous ossification centers inthe face.

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nents.24 The main thrust of growth derives fromthe condylar cartilage proliferation, while masti-catory muscle activity accounts for growth of thecoronoid and angular processes. Developmentof the alveolar process, in both maxilla and man-dible, is predicated on tooth formation.

During intrauterine fetal development, therelative sizes of the maxilla and mandible varywidely. Initially, the mandible is considerablylarger than the maxilla, a predominance laterdiminished by the relatively greater develop-ment of the maxilla, changing the jaw relation-ships from Angle Class III to Class II.25 At about8 weeks post conception, the maxilla overlapsthe mandible. Subsequently, the mandible growsmore rapidly, equaling the maxilla by 11 weekspost conception. Mandibular growth then lagsbetween the 13th and 20th weeks, due to achangeover from Meckels cartilage to the con-dylar secondary cartilage as the main growthcenter of the mandible. At birth, the mandible isgenerally retrognathic to the maxilla, althoughthe two may be of equal size. This retrognathiccondition is usually corrected postnatally byrapid mandibular growth and forward displace-ment to establish an Angle Class I maxilloman-dibular relationship. Inadequate mandibulargrowth results in an Angle Class II (retrogna-thism), and overgrowth produces a Class IIIprognathic profile. The mandible may continueto grow for much longer than the maxilla post-natally, due to the continued presence of thecondylar growth cartilage that uniquely also actsas the articular cartilage of the temporomandib-ular joint.

Conclusions

The clinicians requirement of the anticipatedendpoint of growth and development of the faceto determine whether orthosurgical interven-tion is desirable is one of the great challengeswith which developmental biologists are con-fronted.26 With the increasing identification ofgrowth factors, genes, and chromosomes re-sponsible for development of the face, clinicalgeneticists and orthodontists are now in a betterposition to advise parents of the ultimate out-come of prognosis of various dentofacial malfor-mations and malocclusions of their progeny.The hope of biomimetic intervention by geneticengineering and molecular factor signaling uti-lization in controlling growth, once consideredonly a remote possibility, is now becoming ever

more realistic, as the introduction of alteredgenomes becomes more feasible.27 Nonetheless,much remains to be done for these techniquesto be translated into clinical practice.

AcknowledgmentsAppreciation is expressed for the word processing by JoanneLafrance and the art assistance by Colleen Murdoch.

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Embriologia Articulo