Key Points
-
Embryology, evolution and mouse genetics are shaping our understanding of the development of the head — the most anatomically sophisticated part of the body — and are shedding light on human craniofacial disorders.
-
Human craniofacial disorders arise owing to alterations to specific embryological processes, such as to brain patterning, cell migration, tissue fusion and bone differentiation.
-
The major craniofacial disorders fall into several categories, according to their pattern of malformations, and include: holoprosencephaly, cleft lip and palate, skull vault malformations (such as craniosynostosis), and malformations of the first and second branchial arches, which underlie branchio-oto-renal and Treacher Collins syndromes.
-
Loss-of-function mouse mutants are identifying the types of genes that underlie these categories of malformation and are providing functional insights into the genes that are required for normal craniofacial development.
-
The classes of genes that underlie these disorders range from transcription factors and signalling molecules, the loss of which cause distinct patterning defects, to genes that are required for cell migration and cell proliferation.
-
The most common mechanism that gives rise to craniofacial defects in mice and humans is haploinsufficieny, although gain-of-function mutations in the fibroblast growth factor receptor genes underlie most human craniosynostosis syndromes, such as Apert and Pfeiffer syndromes.
-
Studies of craniofacial malformations show that they often arise from subtle alterations in cell division in the cranial mesenchyme rather than from basic patterning defects. This finding is likely to make it very difficult to identify the genetic determinants of normal variation in facial appearance.
Abstract
The head is anatomically the most sophisticated part of the body and its evolution was fundamental to the origin of vertebrates; understanding its development is a formidable problem in biology. A synthesis of embryology, evolution and mouse genetics is shaping our understanding of head development and in this review we discuss its application to studies of human craniofacial malformations. Many of these disorders have their origins in specific embryological processes, including abnormalities of brain patterning, of the migration and fusion of tissues in the face, and of bone differentiation in the skull vault.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Le Douarin, N. M. & Kalcheim, C. The Neural Crest 2nd edn (Cambridge University Press, Cambridge, 1999).
Gans, C. & Northcutt, R. G. Neural crest and the origin of vertebrates: a new head. Science 220, 268–274 (1983). A classic paper that crystallizes thinking about the importance of the neural crest in vertebrate evolution.
Morriss-Kay, G. Derivation of the mammalian skull vault. J. Anat. (in the press).
Jefferies, R. P. S. in Major Events in Vertebrate Evolution 40–66 (ed. Ahlberg, P. E.) (Systematics Association and Taylor & Francis, London, 2001).
Corbo, J. C., Erives, A., Di Gregorio, A., Chang, A. & Levine, M. Dorsoventral patterning of the vertebrate neural tube is conserved in a protochordate. Development 124, 2335–2344 (1997).
Holland, L. Z. & Holland, N. D. Evolution of neural crest and placodes: Amphioxus as a model for the ancestral vertebrate? J. Anat. (in the press).
Kimmel, C. B., Miller, C. T. & Keynes, R. J. Neural crest patterning and the evolution of the jaw. J. Anat. (in the press).
Ahlberg, P. E. & Milner, A. R. The origin and early diversification of tetrapods. Nature 368, 507–514 (1994).
Chai, Y. et al. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127, 1671–1679 (2000).This paper describes an elegant use of Cre-loxP technology to mark the cranial neural crest, by causing LacZ to be expressed by neural-crest cells.
Hirth, F. & Reichert, H. Conserved genetic programs in insect and mammalian brain development. BioEssays 21, 677–684 (1999).
Butler, A. B. Chordate evolution and the origin of craniates: an old brain in a new head. Anat. Rec. (New Anat.) 261, 111–125 (2000).
Galliot, B. & Miller, D. Origin of anterior patterning. How old is our head? Trends Genet. 16, 1–4 (2000).
Shimeld, S. M. & Holland, P. W. H. Vertebrate innovations. Proc. Natl Acad. Sci. USA 97, 4449–4452 (2000).
Manzanares, M. et al. Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head. Nature 408, 854–857 (2000).A study in which genomic fragments from the 3′ end of the single Hox gene cluster in Amphioxus were assayed for regulatory activity in mice and chicks. Although Amphioxus lacks neural crest, one fragment directed reporter expression to this tissue in both recipient species.
Richman, J. M. & Tickle, C. Epithelial–mesenchymal interactions in the outgrowth of limb buds and facial primordia in chick embryos. Dev. Biol. 154, 299–308 (1992).
Schneider, R. A., Hu, D. & Helms, J. A. From head to toe: conservation of molecular signals regulating limb and craniofacial morphogenesis. Cell Tissue Res. 296, 103–109 (1999).
Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).
Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).This and reference 34 are landmark papers that identified the first genetic basis for HPE in humans. The non-penetrant individual with a SHH mutation in one pedigree exemplifies the unpredictability of many haploinsufficiency phenotypes.
Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8, 269–274 (1994).
Wilkie, A. O. M. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nature Genet. 9, 165–172 (1995).
El Ghouzzi, V. et al. Mutations of the TWIST gene in the Saethre–Chotzen syndrome. Nature Genet. 15, 42–46 (1997).
Howard, T. D. et al. Mutations in TWIST, a basic helix–loop–helix transcription factor, in Saethre–Chotzen syndrome. Nature Genet. 15, 36–41 (1997).
Mavrogiannis, L. A. et al. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nature Genet. 27, 17–18 (2001).This and reference 140 show a link between skull and limb development. Humans heterozygous for an ALX4 mutation have skull-ossification defects but normal limbs; in mice, the identical mutation is associated with extra digits, but a normal skull.
Lohnes, D. et al. Function of the retinoic acid receptors (RARs) during development. I. Craniofacial and skeletal abnormalities in RAR double mutants. Development 120, 2723–2748 (1994).
Orioli, D., Henkemeyer, M., Lemke, G., Klein, R. & Pawson, T. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J. 15, 6035–6049 (1996).
Lu, M. F. et al. prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development 126, 495–504 (1999).
Satokata, I. et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nature Genet. 24, 391–395 (2000).
Trumpp, A., Depew, M. J., Rubenstein, J. L. R., Bishop, J. M. & Martin, G. R. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev. 13, 3136–3148 (1999).
Rossant, J. & Spence, A. Chimeras and mosaics in mouse mutant analysis. Trends Genet. 14, 358–363 (1998).
Nottoli, T., Hagopian-Donaldson, S., Zhang, J., Perkins, A. & Williams, T. AP-2-null cells disrupt morphogenesis of eye, face and limbs in chimeric mice. Proc. Natl Acad. Sci. USA 95, 13714–13719 (1998).
Meyers, E. N., Lewandoski, M. & Martin, G. R. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nature Genet. 18, 136–141 (1998).
Zhou, Y.-X. et al. A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum. Mol. Genet. 9, 2001–2008 (2000).This paper describes a knock-in strategy to target a specific amino-acid substitution to the Fgfr1 gene. This and related approaches are essential to study the gain-of-function mechanisms that occur in certain dominantly inherited mutations, of which the fibroblast growth factor receptors provide several classic examples.
Muenke, M. & Beachy, P. A. in The Metabolic and Molecular Bases of Inherited Disease 8th edn (eds Scriver, C. R. et al.) 6203–6230 (McGraw–Hill, New York, 2001).
Belloni, E. et al. Identification of Sonic Hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14, 353–356 (1996).
Muenke, M. et al. Linkage of a human brain malformation, familial holoprosencephaly, to chromosome 7 and evidence for genetic heterogeneity. Proc. Natl Acad. Sci. USA 91, 8102–8106 (1994).
Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).
Marigo, V. et al. Cloning, expression, and chromosomal location of SHH and IHH : two human homologues of the Drosophila segment polarity gene Hedgehog. Genomics 28, 44–51 (1995).
Wallis, D. & Muenke, M. Mutations in holoprosencephaly. Hum. Mutat. 16, 99–108 (2000).
Wallis, D. E. et al. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nature Genet. 22, 196–198 (1999).
Gripp, K. W. et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nature Genet. 25, 205–208 (2000).
Brown, S. A. et al. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nature Genet. 20, 180–183 (1998).
Oliver, G. et al. Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055 (1995).
Nagai, T. et al. The expression of the mouse Zic1, Zic2, and Zic3 genes suggests an essential role for Zic genes in body pattern formation. Dev. Biol. 182, 299–313 (1997).
Kawakami, K., Sato, S., Ozaki, H. & Ikeda, K. Six family genes — structure and function as transcription factors and their roles in development. BioEssays 22, 616–626 (2000).
Massagué, J., Blain, S. W. & Lo, R. S. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).
Fitzky, B. U. et al. Mutations in the D7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome. Proc. Natl Acad. Sci. USA 95, 8181–8186 (1998).
Wassif, C. A. et al. Mutations in the human sterol D7-reductase gene at 11q12-13 cause Smith–Lemli–Opitz syndrome. Am. J. Hum. Genet. 63, 55–62 (1998).
Waterham, H. R. et al. Smith–Lemli–Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am. J. Hum. Genet. 63, 329–338 (1998).
Kelley, R. I. & Hennekam, R. C. M. The Smith–Lemli–Opitz syndrome. J. Med. Genet. 37, 321–335 (2000).
Porter, J. A., Young, K. E. & Beachy, P. A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274, 255–258 (1996).
Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).
Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).
Nomura, M. & Li, E. Smad2 role in mesoderm formation, left–right patterning and craniofacial development. Nature 393, 786–790 (1998).
Matsuo, I., Kuratani, S., Kimura, C., Takeda, N. & Aizawa, S. Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev. 9, 2646–2658 (1995).Hox genes are not expressed anterior to the second branchial arch or rhombomere 3, so other transcription factors must be involved in patterning more rostral structures. This work identifies Otx2 as having this role in mammals — a role that might be extremely ancient (see references 10 – 12).
DeMyer, W., Zeman, W. & Palmer, C. G. The face predicts the brain: diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 34, 256–263 (1964).
Torres, M., Gómez-Pardo, E. & Gruss, P. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development 122, 3381–3391 (1996).
Beddington, R. S. P. & Robertson, E. J. Axis development and early asymmetry in mammals. Cell 96, 195–209 (1999).An authoritative guide to the molecular control of early development, including head patterning.
Brand, M. et al. Mutations affecting development of the midline and general body shape during zebrafish embryogenesis. Development 123, 129–142 (1996).
Cousley, R. R. J. & Calvert, M. L. Current concepts in the understanding and management of hemifacial microsomia. Br. J. Plast. Surg. 50, 536–551 (1997).
Poswillo, D. The pathogenesis of the first and second branchial arch syndrome. Oral Surg. Oral Med. Oral Pathol. 35, 302–328 (1973).
Naora, H. et al. Transgenic mouse model of hemifacial microsomia: cloning and characterization of insertional mutation region on chromosome 10. Genomics 23, 515–519 (1994).An excellent example of a genetic predisposition to an acquired malformation. A transgene insertion caused a greater than 23-kb deletion, giving rise to hemifacial microsia, but the molecular basis of the predisposition to vessel rupture was not reported.
Kelberman, D. et al. Mapping of a locus for autosomal dominant hemifacial microsomia. J. Med. Genet. 37, S76 (2000).
Abdelhak, S. et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nature Genet. 15, 157–164 (1997).
Xu, P.-X. et al. Eya1 -deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature Genet. 23, 113–117 (1999).
The Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nature Genet. 12, 130–136 (1996).A heroic positional cloning effort, in which the molecular basis of a rare disorder was identified in the absence of any deletions or candidate genes to guide the search.
Dixon, J., Hovanes, K., Shiang, R. & Dixon, M. J. Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1. Hum. Mol. Genet. 6, 727–737 (1997).
Isaac, C. et al. Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome. Mol. Biol. Cell 11, 3061–3071 (2000).
Dixon, J., Brakebusch, C., Fässler, R. & Dixon, M. J. Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum. Mol. Genet. 9, 1473–1480 (2000).
Morriss-Kay, G. M. & Ward, S. J. Retinoids and mammalian development. Int. Rev. Cytol. 188, 73–131 (1999).
Schutte, B. C. & Murray, J. C. The many faces and factors of orofacial clefts. Hum. Mol. Genet. 8, 1853–1859 (1999).
Lidral, A. C. et al. Association of MSX1 and TGFβ3 with nonsyndromic clefting in humans. Am. J. Hum. Genet. 63, 557–568 (1998).
Prescott, N. J., Lees, M. M., Winter, R. M. & Malcolm, S. Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs. Hum. Genet. 106, 345–350 (2000).
Quaderi, N. A. et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nature Genet. 17, 285–291 (1997).
Cox, T. C. et al. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum. Mol. Genet. 9, 2553–2562 (2000).
Celli, J. et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99, 143–153 (1999).Dominant mutations of this p53 homologue have been identified in several related syndromes, affecting the skin, limbs and face. This provides, for the first time, a rational basis for classifying a clinically confusing group of disorders.
Van den Boogaard, M.-J. H., Dorland, M., Beemer, F. A. & Ploos van Amstel, H. K. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nature Genet. 24, 342–343 (2000).
Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–355 (1994).
Suzuki, K. et al. Mutations of PVRL1, encoding a cell–cell adhesion molecule/herpesvirus receptor, in cleft lip/palate–ectodermal dysplasia. Nature Genet. 25, 427–430 (2000).
Halford, M. M. et al. Ryk -deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature Genet. 25, 414–418 (2000).
Halford, M. M. & Stacker, S. A. Revelations of the RYK receptor. BioEssays 23, 34–45 (2001).
Barrow, J. R. & Capecchi, M. R. Compensatory defects associated with mutations in Hoxa1 restore normal palatogenesis to Hoxa2 mutants. Development 126, 5011–5026 (1999).
Scambler, P. J. The 22q11 deletion syndromes. Hum. Mol. Genet. 9, 2421–2426 (2000).
Ryan, A. K. et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J. Med. Genet. 34, 798–804 (1997).
Zori, R. T. et al. Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency. Am. J. Med. Genet. 77, 8–11 (1998).
Lindsay, E. A. et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001).
Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).
Merscher, S. et al. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104, 619–629 (2001).
Lindsay, E. A. et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401, 379–383 (1999).
Vikkula, M. et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 80, 431–437 (1995).
Hastbacka, J. et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073–1087 (1994).
Kaartinen, V., Cui, X. M., Heisterkamp, N., Groffen, J. & Shuler, C. F. Transforming growth factor-β3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane. Dev. Dynam. 209, 255–260 (1997).
Sun, D., Vandergurg, C. R., Odierna, G. S. & Hay, E. TGF-β3 promotes transformation of chicken palate medial edge epithelium to mesenchyme in vitro. Development 125, 95–105 (1998).
Taya, Y., O'Kane, S. & Ferguson, M. W. J. Pathogenesis of cleft palate in TGF-β3 knockout mice. Development 126, 3869–3879 (1999).
Reardon, W. et al. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature Genet. 8, 98–103 (1994).
Bellus, G. A. et al. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nature Genet. 14, 174–176 (1996).
Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nature Rev. Genet. 1, 40–47 (2000).
Muenke, M. & Wilkie, A. O. M. in The Metabolic and Molecular Bases of Inherited Disease 8th edn (eds Scriver, C. R. et al.) 6117–6146 (McGraw–Hill, New York, 2001).
Neilson, K. M. & Friesel, R. E. Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome. J. Biol. Chem. 270, 26037–26040 (1995).
Robertson, S. C. et al. Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. Proc. Natl Acad. Sci. USA 95, 4567–4572 (1998).
Anderson, J., Burns, H. D., Enriquez-Harris, P., Wilkie, A. O. M. & Heath, J. K. Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Hum. Mol. Genet. 7, 1475–1483 (1998).
Yu, K., Herr, A. B., Waksman, G. & Ornitz, D. M. Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc. Natl Acad. Sci. USA 97, 14536–14541 (2000).This paper indicated that specific mutations in the extracellular region of FGFR2 confer a gain of function by increasing the repertoire of ligands that receptor isoforms can bind.
Oldridge, M. et al. De novo Alu element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome. Am. J. Hum. Genet. 64, 446–461 (1999).
Hajihosseini, M. K., Wilson, S., De Moerlooze, L. & Dickson, C. A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes. Proc. Natl Acad. Sci. USA 98, 3855–3860 (2001).
Johnson, D. et al. A comprehensive screen for TWISTmutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1. Am. J. Hum. Genet. 63, 1282–1293 (1998).
El Ghouzzi, V. et al. Mutations in the basic domain and the loop–helix II junction of TWIST abolish DNA binding in Saethre–Chotzen syndrome. FEBS Lett. 492, 112–118 (2001).
Hamamori, Y. et al. Regulation of histone acetyltranferases p300 and PCAF by the bHLH protein Twist and adenoviral oncoprotein E1A. Cell 96, 405–413 (1999).This paper provides a mechanistic explanation for the transcription-inhibitory properties of TWIST by showing that the amino-terminal segment specifically binds to histone acetyltransferases, which relieve the repressive effects of chromatin.
Johnson, D., Iseki, S., Wilkie, A. O. M. & Morriss-Kay, G. M. Expression patterns of Twist and Fgfr1, -2 and -3 in the developing mouse coronal suture suggest a key role for Twist in suture initiation and biogenesis. Mech. Dev. 91, 341–345 (2000).
Rice, D. P. C. et al. Integration of FGF and TWIST in calvarial bone and suture development. Development 127, 1845–1855 (2000).
Iseki, S., Wilkie, A. O. M. & Morriss-Kay, G. M. Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault. Development 126, 5611–5620 (1999).
Shishido, E., Higashijima, S.-i., Emori, Y. & Saigo, K. Two FGF-receptor homologues of Drosophila: one is expressed in mesodermal primordium in early embryos. Development 117, 751–761 (1993).
Jabs, E. W. et al. A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75, 443–450 (1993).
Ma, L., Golden, S., Wu, L. & Maxson, R. The molecular basis of Boston-type craniosynostosis: the Pro148–His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. Hum. Mol. Genet. 5, 1915–1920 (1996).
Wilkie, A. O. M. et al. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nature Genet. 24, 387–390 (2000).
Wuyts, W. et al. Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna. Hum. Mol. Genet. 9, 1251–1255 (2000).
Wuyts, W. et al. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). J. Med. Genet. 37, 916–920 (2000).
Carlton, M. B. L., Colledge, W. H. & Evans, M. J. Crouzon-like craniofacial dysmorphology in the mouse is caused by an insertional mutation at the Fgf3/Fgf4 locus. Dev. Dynam. 21, 242–249 (1998).
Bourgeois, P. et al. The variable expressivity and incomplete penetrance of the TWIST-null heterozygous mouse phenotype resemble those of human Saethre–Chotzen syndrome. Hum. Mol. Genet. 7, 945–957 (1998).
Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–779 (1997).
Opperman, L. A. Cranial sutures as intramembranous bone growth sites. Dev. Dynam. 219, 472–485 (2000).
Fleming, A. & Copp, A. J. Embryonic folate metabolism and mouse neural tube defects. Science 280, 2107–2109 (1998).
Kraus, P. & Lufkin, T. Mammalian DIx homeobox gene control of craniofacial and inner ear morphogenesis. J. Cell. Biochem. 32/33, S133–S140 (1999).
Clouthier, D. E. et al. Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice. Dev. Biol. 217, 10–24 (2000).
Price, J. A., Bowden, D. W., Wright, J. T., Pettenati, M. J. & Hart, T. C. Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Hum. Mol. Genet. 7, 563–569 (1998).
Hofstra, R. M. et al. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am. J. Hum. Genet. 64, 304–308 (1999).
Brewer, C., Holloway, S., Zawalnyski, P., Schinzel, A. & FitzPatrick, D. A chromosomal deletion map of human malformations. Am. J. Hum. Genet. 63, 1153–1159 (1998).
Brewer, C., Holloway, S., Zawalnyski, P., Schinzel, A. & FitzPatrick, D. A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality — and tolerance of segmental aneuploidy — in humans. Am. J. Hum. Genet. 64, 1704–1708 (1999).
Winter, R. M. What's in a face? Nature Genet. 12, 124–129 (1996).
Tangchaitrong, K., Messer, L. B., Thomas, C. D. & Townsend, G. C. Fourier analysis of facial profiles of young twins. Am. J. Phys. Anthropol. 113, 369–379 (2000).
Juriloff, D. M. & Harris, M. J. Mouse models for neural tube closure defects. Hum. Mol. Genet. 9, 993–1000 (2000).
Francis-West, P., Ladher, R., Barlow, A. & Graveson, A. Signalling interactions during facial development. Mech. Dev. 75, 3–28 (1998).
Gendron-Maguire, M., Mallo, M., Zhang, M. & Gridley, T. Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75, 1317–1331 (1993).
Rijli, F. M. et al. A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell 75, 1333–1349 (1993).
Jiang, R. et al. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev. 12, 1046–1057 (1998).
Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial–mesenchymal interaction. Nature Genet. 11, 415–421 (1995).
Proetzel, G. et al. Transforming growth factor-β3 is required for secondary palate fusion. Nature Genet. 11, 409–414 (1995).
Wassif, C. A. et al. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Hum. Mol. Genet. 10, 555–564 (2001).
Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).
Li, Y. et al. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell 80, 423–430 (1995).
Richards, A. J. et al. A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in α1 (XI) collagen. Hum. Mol. Genet. 5, 1339–1343 (1996).
Qu, S. et al. Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly. Development 125, 2711–2721 (1998).
Acknowledgements
A.O.M.W. is funded by the Wellcome Trust (Senior Research Fellowship in Clinical Science) and G.M.M.K.'s work is funded by Action Research. We thank anonymous reviewers for their comments.
Author information
Authors and Affiliations
Related links
Related links
DATABASE LINKS
ectrodactyly, ectodermal dysplasia and cleft lip/palate
Atlas and Database of Human Developmental Anatomy
FURTHER INFORMATION
Glossary
- NEURAL PLATE
-
The initial group of neuroepithelial cells that forms as a result of neural induction. These cells give rise to the neural tube and ultimately to the central nervous system.
- TUNICATE
-
A primitive chordate, typified by ascidians (sea squirts).
- NOTOCHORD
-
An axial, rod-like structure in vertebrates, which provides rigidity to the early embryo and later contributes to the intervertebral discs. It is the only rigid skeletal structure in extant non-vertebrate chordates.
- CHORDATES
-
Members of the phylum Chordata, which comprises animals with a notochord and includes all vertebrates.
- BRANCHIAL ARCHES
-
Also known as pharyngeal arches. Literally means a gill-supporting structure. They are present in modified form in all vertebrate embryos as a series of tissues that give rise to structures of the face, ear and neck.
- TETRAPODS
-
Vertebrate animals with four limbs, and their limbless descendants.
- OSSICLES
-
The small bones of the middle ear (the malleus, incus and stapes) that transmit sound impulses from the eardrum to the inner ear.
- HOMEODOMAIN
-
A highly conserved sequence motif, usually comprising 60 amino acids, that includes a DNA-binding region.
- IMPLANTATION
-
Attachment to, and invasion of, the uterine wall by the late-preimplantation-stage embryo (blastocyst).
- TELENCEPHALON
-
The most anterior part of the brain, which gives rise to the cerebral hemispheres.
- HYPOMORPH
-
A mutant allele that does not completely eliminate the wild-type function of a gene and gives a less severe phenotype than a loss-of-function mutant.
- HOLOPROSENCEPHALY
-
Failure of the forebrain (prosencephalon) to divide into hemispheres or lobes, often accompanied by a deficit in midline facial development.
- CYCLOPIA
-
A single, central eye.
- CONDUCTIVE HEARING LOSS
-
Hearing loss caused by loss of the external ear canal or malformation of the ossicular apparatus.
- EXENCEPHALY
-
Failure of the cranial component of the neural tube to close.
- HOMEOTIC TRANSFORMATION
-
When one embryonic axial segment alters its identity to that of another.
- PRIMARY PALATE
-
The part of the palate that develops from the fusion of the medial nasal swellings of the face.
- SECONDARY PALATE
-
The part of the palate that develops from the fusion of the palatal shelves, which undergo complex movements; this occurs later than primary palate formation.
- MESENCHYME
-
Embryonic tissue composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.
- HYOGLOSSUS MUSCLE
-
The muscle of the tongue.
Rights and permissions
About this article
Cite this article
Wilkie, A., Morriss-Kay, G. Genetics of craniofacial development and malformation. Nat Rev Genet 2, 458–468 (2001). https://doi.org/10.1038/35076601
Issue Date:
DOI: https://doi.org/10.1038/35076601
This article is cited by
-
Craniofacial therapy: advanced local therapies from nano-engineered titanium implants to treat craniofacial conditions
International Journal of Oral Science (2023)
-
ExDarkLBP: a hybrid deep feature generation-based genetic malformation detection using facial images
Multimedia Tools and Applications (2023)
-
STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis
Nature Communications (2021)
-
Insights and future directions of potential genetic therapy for Apert syndrome: A systematic review
Gene Therapy (2021)
-
FACEts of mechanical regulation in the morphogenesis of craniofacial structures
International Journal of Oral Science (2021)
