Vertebrate Embryo: Craniofacial Development


Craniofacial development requires the co‐ordinated integration of signals from the endoderm, mesoderm, ectoderm, neuroectoderm and neural crest cells (NCCs). Reflecting this complexity, craniofacial abnormalities are leading causes of birth defects and infant mortality. As the craniofacial complex shares tissue origins with the heart, craniofacial defects are often linked to cardiac defects. The key steps in craniofacial development and evolution include the generation, migration and differentiation of NCCs, and the dynamic interplay between signals in the NCC and the endoderm, ectoderm and mesoderm. The NCC determine species diversity whilst signals from the endoderm determine which facial structures are formed. Reflecting the evolutionary novelty of the head, the mechanisms of musculoskeletal development are also distinct from the trunk.

Key Concepts

  • The vertebrate head arose due to the evolution of neural crest and sensory placodes.
  • Neural crest cells are a transient population of multipotent cells that give rise to most of the derivatives of the face and neck.
  • The neck and lower jaw are formed from pharyngeal arches, transient structures that arise in a rostral‐caudal sequence. The pharyngeal arches initially consist of mesoderm, ectoderm, endoderm and neural crest. Each of these tissue layers gives rise to different derivatives.
  • The cranial neural crest arises from the forebrain, midbrain and hindbrain. The neural crest streams migrate along stereotypical paths into the developing face and pharyngeal arches.
  • Patterning of the pharyngeal arches 2, 3, 4 and 6 is determined by Hox genes.
  • The developing face (pharyngeal arch 1 or mandibular primordia, maxillary primordia, lateral and medial processes) does not express Hox genes. The face is patterned by homeobox genes.
  • Growth factors, for example SHH, FGF8, ENDOTHELIN‐1 and BMP4 control the growth of the face (cell survival and proliferation) through epithelial–mesenchymal signalling interactions and patterning via regulation of homeobox gene expression.
  • Signals from the early endoderm pattern the facial primordia, for example medial nasal process (nasal septum) versus the mandibular primordia (Meckel's cartilage).
  • The neural crest determines the shape of the face, that is characteristic species shape. These effects are mediated, in part, by BMP4 expression and the positioning of the FEZ, a growth zone in the upper face.
  • The cranial mesoderm and cranial NCC are required for both the development of the head and heart and therefore, cardiac and craniofacial abnormalities often occur together. The development of some cardiac muscles and cranial striated muscles has shared molecular requirements.

Keywords: craniofacial development; facial patterning; neural crest; Treacher Collin's syndrome; craniofacial evolution

Figure 1. Neural crest development. Schematics of neural crest development from the establishment of the neural border containing the neural crest progenitors within the neuroectoderm (a, b), epithelial–mesenchymal transformation and migration of NCC (neural crest cells) (d) and the migration routes taken by NCC to reach the developing face and pharyngeal arches (e). (c) The mechanisms of Treacher Collin's syndrome. In (a–d), the neuroectoderm is shown in blue, with the NCC progenitors/NCC in dark blue. The preplacodal region (PPR) is shown in purple and the ectoderm in orange. Specifically, (a, b) NCC specification within the neuroectoderm of an early mouse or chick embryo; (b) is a cross section of the embryo shown in (a) at the level of the dashed line. The NCC arise at the border of the neuroectoderm. In the head, this domain is surrounded by the preplacodal domain. (c) The neuroectoderm is characterised by high levels of reactive oxgen species (ROS); this can lead to DNA (deoxyribonucleic acid) damage within the neuroectoderm, which is normally repaired (LHS of image). Repair requires TCOF1. In Treacher Collins syndrome, is mutated, and this repair does not happen. This leads to cell stress and the activation of the tumour suppressor, P53. P53 decreases cell proliferation and induces apoptosis: consequently, fewer NCC are generated. (d) Epithelial–mesenchymal transformation of NCC, the alteration in cadherin expression and start of migration which is partly controlled by N‐Cadherin expression and Wnt‐PCP through the regulation of RhoA/Rac1 activity. In cells at the front of the migratory stream, RhoA/Rac1 activity is polarised across the cell which drives cell migration forward. (e) A sagittal view of an E9.5 mouse embryo showing routes of NCC migration into the pharyngeal arches and developing face from the distinct rhombomeres (r) of the hindbrain, mesencephalon (midbrain) and prosencephalon (forebrain). Very few NCC are produced by R3 and R5; those that are generated join adjacent NCC streams. Subdivisions of the forebrain: di, diencephalon; te, telencephalon. Some derivatives of the PPR are also indicated: l, lens; ov, otic vesicle and olf (olfactory placode). Fnp, frontonasal process; Hp, heart primordia; Mx, maxillary process and Pa, pharyngeal arch.
Figure 2. Structure of the pharyngeal arches and facial primordia. (a) Saggital view of an E10.5 mouse embryo showing the cranial ganglia which are formed from neural crest and the epibranchial placodes (indicated by purple). Other placodal derivatives (l, lens; ov, otic vesicle and olf, olfactory placode) are also shown. (b) A cross section through pharyngeal arches 1 and 2 with the ectoderm on the outside and endoderm on the inside. The arches are separated by clefts (ectodermal side) and pouches (endodermal side). Each arch contains mesoderm, which gives rise to striated muscle and endothelial cells, encapsulated by NCC, which gives rise to a cartilaginous skeletal element (together with other derivatives). Each arch also contains an artery. (c, d) Frontal views of the facial processes at an early (c) and later (d) time of development. Initially, the facial processes are small and have not fused. These processes will grow and merge to generate the final face. (e) Frontal view of a developing face showing the FEZ domain, and the regulation of , and homeobox genes in the mesenchyme by the differential expression of FGF8, BMP4 and ENDOTHELIN1. Md, mandibular prominence; Mx, maxillary prominence; PA, pharyngeal arch.
Figure 3. Molecular regulation of facial patterning. Saggital views of the developing face and pharyngeal arches. (a, b, e) Each pharyngeal arch, the maxillary and mandibular primordia give rise to distinct skeletal elements. (a, e) Pharyngeal arches 2, 3, 4 and 6 are characterised by a unique combination of HOX genes which are expressed in a nested domain along the anterior–posterior axis. For example, the second pharyngeal arch expresses HOXA2 but not HOXA3,B3/D3 or HOXA4/D4. (a, b, e) The facial primordia are HOX ‘free’ and are characterised by homeobox gene expression: the mandibular primordium expresses DLX5/DLX6, whereas the maxillary primordium lacks DLX5/6 expression. (c) Gene inactivation of or , which regulates expression, transforms the mandibular primordia to the maxillary primordia. (d) Conversely gain of ENDOTHELIN‐1 signalling (which induces expression) or the expression of , a transcriptional mediator of function, in the maxillary primordia transforms the maxillary primordia to the mandibular primordia. (f) HOXA2 is required for development of the second pharyngeal arch: in the absence of HOXA2, the second pharyngeal arch forms proximal first arch skeletal structures, that is part of Meckel's cartilage, the incus and malleus bones. Fnp, frontonasal process; GOF, gain of function; I, incus; M, malleus; Md, mandibular prominence; Mx, maxillary prominence; PA, pharyngeal arch.
Figure 4.Cut andpasteexperiments showing the role of the NCC and endoderm during facial development. (a, b) Transplantation of premigratory NCC from a quail to a duck embryo or vice versa results in the development of a duck host with a quail head or a quail host with a duck head, respectively. The NCC also patterns the overlying ectodermal structures as illustrated here by the formation of the crest in the duck host in response to the quail NCC. This ‘quail‐like’ structure is formed from the duck ectoderm. Similarly, in a duck NCC to quail host chimera, the head plumage, which arises from the quail ectoderm, resembles a duck. (c–e) The endoderm, initially the most ventral tissue layer (c) comes into contact with the NCC as they migrate (c) and once they have reached the facial primordia and pharyngeal arches (e). Each region of endoderm is associated with the development of distinct skeletal structures (e). Transplantation of endoderm to an ectopic location (d) results in the formation of an ectopic skeletal structure corresponding to the region of endoderm transplanted (and not to the responding NCC population) (f). Fnp, frontonasal process and PA, pharyngeal arches; Mes, mesencephalon; Pros, prosencephalon; Rho, rhombocephalon. (c–e) Modified with permission from Ruhin et al. (2003) © John Wiley and Sons.
Figure 5. Craniofacial musculoskeletal development. (a–c) Alizarin‐red staining showing the developing membrane bones (red) in E14.5, E16.5 and E18.5 fetal mice. At E14.5, the frontal (f) and parietal bones (p) have just formed and are expanding by deposition of new osteoblasts (arrows). Once the bones have met (c), they grow at sutures. The frontal bone is NCC derived, while the parietal bone is mesoderm derived. The coronal suture forms from the mesoderm (indicated by dashed line) and sets a boundary between these two bones. The mandibular bone (Md), in contrast, grows by remodelling, that is deposition and removal of bone to alter its size and shape and by growth of secondary cartilages at the tips of the bone. (d, e) Schematic of the developing suture showing the expression of key regulators of suture maintenance and osteoblast differentiation. Osteoblasts differentiate in response to high level of FGF and BMP signalling and high levels of RUNX2 expression. Gain of function mutations in or or increased expression/activity of RUNX2 (e.g. increased copies of ), loss of function in TWIST (which normally inhibits RUNX2) enhance osteoblast differentiation leading to craniosynostosis. (f) Schematic showing the key regulators of myogenic differentiation for the different craniofacial muscles. PITX2 is required for the extraocular muscles (EOM), TBX1 for some lower jaw muscles (first arch derivatives) and the muscles of facial expression (second arch derivatives) and both TBX1 and PITX2 for the muscles of mastication (mast). Both TBX1 and PITX2 are also required for cardiac muscle development from the secondary heart field (SFH indicates SFH origin of cardiac muscles). In mice, striated oesophageal muscles (SOM) also arise from the cranial mesoderm and require TBX1 for their development. The muscles of facial expression move into the facial primordia by an unknown mechanism (white arrow). n, nasal bone; Md, mandibular bone; mx, maxilla bone; pmx, premaxillary bone.


Abitua PB, Wagner E, Navarrete IA and Levine M (2012) Identification of a rudimentary neural crest in a non‐vertebrate chordate. Nature 492: 104–107.

Abitua PB, Gainous TB, Kaczmarczyk AN, et al. (2015) The pre‐vertebrate origins of neurogenic placodes. Nature 524: 462–465.

Abzhanov A, Protas M, Grant BR, Grant PR and Tabin CJ (2004) Bmp4 and morphological variation of beaks in Darwin's finches. Science 305: 1462–1465.

Abzhanov A, Kuo WP, Hartmann C, et al. (2006) The calmodulin pathway and evolution of elongated beak morphology in Darwin's finches. Nature 442: 563–567.

Albertson RC, Streelman JT, Kocher TD and Yelick PC (2005) Integration and evolution of the cichlid mandible: the molecular basis of alternate feeding strategies. Proceedings of the National Academy of Sciences of the United States of America 102: 16287–16292.

Baggiolini A, Varum S, Mateos JM, et al. (2015) Premigratory and migratory neural crest cells are multipotent in vivo. Cell Stem Cell 16: 314–322.

Baltzinger M, Ori M, Pasqualetti M, Nardi I and Rijli FM (2005) Hoxa2 knockdown in Xenopus results in hyoid to mandibular homeosis. Developmental Dynamics 234: 858–867.

Barlow AJ and Francis‐West PH (1997) Ectopic application of recombinant BMP‐2 and BMP‐4 can change patterning of developing chick facial primordia. Development 124: 391–398.

Beverdam A, Merlo GR, Paleari L, et al. (2002) Jaw transformation with gain of symmetry after Dlx5/Dlx6 inactivation: mirror of the past? Genesis 34: 221–227.

Bhatt S, Diaz R and Trainor PA (2013) Signals and switches in Mammalian neural crest cell differentiation. Cold Spring Harbor Perspectives in Biology 5. pii: a008326.

Billmyre KK and Klingensmith J (2015) Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation. Developmental Dynamics 244: 564–576.

Brito JM, Teillet MA and Le Douarin NM (2006) An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival. Proceedings of the National Academy of Sciences of the United States of America 103: 11607–11612.

Brito JM, Teillet MA and Le Douarin NM (2008) Induction of mirror‐image supernumerary jaws in chicken mandibular mesenchyme by Sonic Hedgehog‐producing cells. Development 135: 2311–2319.

Bronner ME and Le Douarin NM (2012) Development and evolution of the neural crest: an overview. Developmental Biology 366: 2–9.

Bronner ME and Simoes‐Costa M (2016) The neural crest migrating into the twenty‐first century. Current Topics in Developmental Biology 116: 115–134.

Bronner‐Fraser M and Fraser SE (1988) Cell lineage analysis reveals multipotency of some avian neural crest cells. Nature 335: 161–164.

Bronner‐Fraser M and Fraser S (1989) Developmental potential of avian trunk neural crest cells in situ. Neuron 3: 755–766.

Buitrago‐Delgado E, Nordin K, Rao A, Geary L and LaBonne C (2015) NEURODEVELOPMENT. Shared regulatory programs suggest retention of blastula‐stage potential in neural crest cells. Science 348: 1332–1335.

Casaca A, Santos AC and Mallo M (2014) Controlling Hox gene expression and activity to build the vertebrate axial skeleton. Developmental Dynamics 243: 24–36.

Cebra‐Thomas JA, Terrell A, Branyan K, et al. (2013) Late‐emigrating trunk neural crest cells in turtle embryos generate an osteogenic ectomesenchyme in the plastron. Developmental Dynamics 242: 1223–1235.

Cela P, Buchtova M, Vesela I, et al. (2016) BMP signaling regulates the fate of chondro‐osteoprogenitor cells in facial mesenchyme in a stage‐specific manner. Developmental Dynamics 245 (9): 947–962.

Clark K, Bender G, Murray BP, et al. (2001) Evidence for the neural crest origin of turtle plastron bones. Genesis 31: 111–117.

Clay MR and Halloran MC (2014) Cadherin 6 promotes neural crest cell detachment via F‐actin regulation and influences active Rho distribution during epithelial‐to‐mesenchymal transition. Development 141: 2506–2515.

Clouthier DE, Garcia E and Schilling TF (2010) Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. American Journal of Medical Genetics. Part A 152A: 2962–2973.

Couly GF, Coltey PM and Le Douarin NM (1993) The triple origin of skull in higher vertebrates: a study in quail‐chick chimeras. Development 117: 409–429.

Couly G, Creuzet S, Bennaceur S, Vincent C and Le Douarin NM (2002) Interactions between Hox‐negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 129: 1061–1073.

Creuzet SE (2009) Neural crest contribution to forebrain development. Seminars in Cell and Developmental Biology 20: 751–759.

Dauwerse JG, Dixon J, Seland S, et al. (2011) Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nature Genetics 43: 20–22.

Depew MJ, Lufkin T and Rubenstein JL (2002) Specification of jaw subdivisions by Dlx genes. Science 298: 381–385.

Dixon J, Brakebusch C, Fassler R and Dixon MJ (2000) Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Human Molecular Genetics 9: 1473–1480.

Dixon J and Dixon MJ (2004) Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle. Developmental Dynamics 229: 907–914.

Dixon J, Jones NC, Sandell LL, et al. (2006) Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proceedings of the National Academy of Sciences of the United States of America 103: 13403–13408.

Dixon MJ, Marazita ML, Beaty TH and Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews. Genetics 12: 167–178.

Duband JL, Dady A and Fleury V (2015) Resolving time and space constraints during neural crest formation and delamination. Current Topics in Developmental Biology 111: 27–67.

Dyer LA and Kirby ML (2009) The role of secondary heart field in cardiac development. Developmental Biology 336: 137–144.

Ealba EL, Jheon AH, Hall J, et al. (2015) Neural crest‐mediated bone resorption is a determinant of species‐specific jaw length. Developmental Biology 408: 151–163.

Eames BF and Schneider RA (2005) Quail‐duck chimeras reveal spatiotemporal plasticity in molecular and histogenic programs of cranial feather development. Development 132: 1499–1509.

Etchevers HC, Vincent C, Le Douarin NM and Couly GF (2001) The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128: 1059–1068.

Fondon JW 3rd and Garner HR (2004) Molecular origins of rapid and continuous morphological evolution. Proceedings of the National Academy of Sciences of the United States of America 101: 18058–18063.

Fukuhara S, Kurihara Y, Arima Y, Yamada N and Kurihara H (2004) Temporal requirement of signaling cascade involving endothelin‐1/endothelin receptor type A in branchial arch development. Mechanisms of Development 121: 1223–1233.

Funato N, Kokubo H, Nakamura M, Yanagisawa H and Saga Y (2016) Specification of jaw identity by the Hand2 transcription factor. Scientific Reports 6: 28405.

Gans C and Northcutt RG (1983) Neural crest and the origin of vertebrates: a new head. Science 220: 268–273.

Gendron‐Maguire M, Mallo M, Zhang M and Gridley T (1993) Hoxa‐2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest. Cell 75: 1317–1331.

Gopalakrishnan S, Comai G, Sambasivan R et al. (2015) A Cranial Mesoderm Origin for Esophagus Striated Muscles. Dev Cell 34 (6): 694–704. DOI: 10.1016/j.devcel.2015.07.003

Grammatopoulos GA, Bell E, Toole L, Lumsden A and Tucker AS (2000) Homeotic transformation of branchial arch identity after Hoxa2 overexpression. Development 127: 5355–5365.

Green SA, Simoes‐Costa M and Bronner ME (2015) Evolution of vertebrates as viewed from the crest. Nature 520: 474–482.

Hall J, Jheon AH, Ealba EL, et al. (2014) Evolution of a developmental mechanism: species‐specific regulation of the cell cycle and the timing of events during craniofacial osteogenesis. Developmental Biology 385: 380–395.

Harel I, Maezawa Y, Avraham R, et al. (2012) Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 109: 18839–18844.

Hu D, Marcucio RS and Helms JA (2003) A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 130: 1749–1758.

Hu D and Marcucio RS (2009a) A SHH‐responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development 136: 107–116.

Hu D and Marcucio RS (2009b) Unique organization of the frontonasal ectodermal zone in birds and mammals. Developmental Biology 325: 200–210.

Hu D, Young NM, Xu Q, et al. (2015) Signals from the brain induce variation in avian facial shape. Developmental Dynamics 244 (9): 1133–1143.

Hunter MP and Prince VE (2002) Zebrafish hox paralogue group 2 genes function redundantly as selector genes to pattern the second pharyngeal arch. Developmental Biology 247: 367–389.

Jacob C (2015) Transcriptional control of neural crest specification into peripheral glia. Glia 63 (11): 1883–1896.

Jiang X, Iseki S, Maxson RE, Sucov HM and Morriss‐Kay GM (2002) Tissue origins and interactions in the mammalian skull vault. Developmental Biology 241: 106–116.

Jones NC, Lynn ML, Gaudenz K, et al. (2008) Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature Medicine 14: 125–133.

Kaltschmidt B, Kaltschmidt C and Widera D (2012) Adult craniofacial stem cells: sources and relation to the neural crest. Stem Cell Reviews 8: 658–671.

Kaukua N, Shahidi MK, Konstantinidou C, et al. (2014) Glial origin of mesenchymal stem cells in a tooth model system. Nature 513: 551–554.

Kelly RG, Buckingham ME and Moorman AF (2014) Heart fields and cardiac morphogenesis. Cold Spring Harbor Perspectives in Medicine 4. pii: a015750.

Keyte AL, Alonzo‐Johnsen M and Hutson MR (2014) Evolutionary and developmental origins of the cardiac neural crest: building a divided outflow tract. Birth Defects Research. Part C, Embryo Today 102: 309–323.

Kim J, Lo L, Dormand E and Anderson DJ (2003) SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells. Neuron 38: 17–31.

Kohli SS and Kohli VS (2012) A comprehensive review of the genetic basis of cleft lip and palate. Journal of Oral and Maxillofacial Pathology 16: 64–72.

Krispin S, Nitzan E, Kassem Y and Kalcheim C (2010) Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest. Development 137: 585–595.

Kulesa PM and McLennan R (2015) Neural crest migration: trailblazing ahead. F1000Prime Reports 7: 02.

Lan Y, Xu J and Jiang R (2015) Cellular and molecular mechanisms of palatogenesis. Current Topics in Developmental Biology 115: 59–84.

Langeland JA, Tomsa JM, Jackman WR Jr and Kimmel CB (1998) An amphioxus snail gene: expression in paraxial mesoderm and neural plate suggests a conserved role in patterning the chordate embryo. Development Genes and Evolution 208: 569–577.

Le Douarin NM and Dupin E (2016) The pluripotency of neural crest cells and their role in brain development. Current Topics in Developmental Biology 116: 659–678.

Lee SH, Fu KK, Hui JN and Richman JM (2001) Noggin and retinoic acid transform the identity of avian facial prominences. Nature 414: 909–912.

Lescroart F, Hamou W, Francou A, et al. (2015) Clonal analysis reveals a common origin between nonsomite‐derived neck muscles and heart myocardium. Proceedings of the National Academy of Sciences of the United States of America 112: 1446–1451.

Liu W, Selever J, Murali D, et al. (2005) Threshold‐specific requirements for Bmp4 in mandibular development. Developmental Biology 283: 282–293.

Mallarino R, Campas O, Fritz JA, et al. (2012) Closely related bird species demonstrate flexibility between beak morphology and underlying developmental programs. Proceedings of the National Academy of Sciences of the United States of America 109: 16222–16227.

Mallo M, Wellik DM and Deschamps J (2010) Hox genes and regional patterning of the vertebrate body plan. Developmental Biology 344: 7–15.

Marcucio RS, Cordero DR, Hu D and Helms JA (2005) Molecular interactions coordinating the development of the forebrain and face. Developmental Biology 284: 48–61.

Maruyama T, Jeong J, Sheu TJ and Hsu W (2016) Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration. Nature Communications 7: 10526.

Maxhimer JB, Bradley JP and Lee JC (2015) Signaling pathways in osteogenesis and osteoclastogenesis: lessons from cranial sutures and applications to regenerative medicine. Genes & Diseases 2: 57–68.

Mayor R and Theveneau E (2013) The neural crest. Development 140: 2247–2251.

Mayor R and Theveneau E (2014) The role of the non‐canonical Wnt‐planar cell polarity pathway in neural crest migration. Biochemical Journal 457: 19–26.

McBratney‐Owen B, Iseki S, Bamforth SD, Olsen BR and Morriss‐Kay GM (2008) Development and tissue origins of the mammalian cranial base. Developmental Biology 322: 121–132.

McGonnell IM and Graham A (2002) Trunk neural crest has skeletogenic potential. Current Biology 12: 767–771.

McKinney MC, Fukatsu K, Morrison J, et al. (2013) Evidence for dynamic rearrangements but lack of fate or position restrictions in premigratory avian trunk neural crest. Development 140: 820–830.

Merrill AE, Eames BF, Weston SJ, Heath T and Schneider RA (2008) Mesenchyme‐dependent BMP signaling directs the timing of mandibular osteogenesis. Development 135: 1223–1234.

Michailovici I, Eigler T and Tzahor E (2015) Craniofacial Muscle Development. Current Topics in Developmental Biology 115: 3–30.

Minoux M, Antonarakis GS, Kmita M, Duboule D and Rijli FM (2009) Rostral and caudal pharyngeal arches share a common neural crest ground pattern. Development 136: 637–645.

Minoux M and Rijli FM (2010) Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137: 2605–2621.

Mirando AJ, Maruyama T, Fu J, Yu HM and Hsu W (2010) beta‐Catenin/cyclin D1 mediated development of suture mesenchyme in calvarial morphogenesis. BMC Developmental Biology 10: 116.

Mundell NA and Labosky PA (2011) Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates. Development 138: 641–652.

Munoz WA and Trainor PA (2015) Neural crest cell evolution: how and when did a neural crest cell become a neural crest cell. Current Topics in Developmental Biology 111: 3–26.

Neeb Z, Lajiness JD, Bolanis E and Conway SJ (2013) Cardiac outflow tract anomalies. Wiley Interdisciplinary Reviews. Developmental Biology 2: 499–530.

Noden DM (1988) Interactions and fates of avian craniofacial mesenchyme. Development 103 (Suppl): 121–140.

Noden DM (1990) Origins and assembly of avian embryonic blood vessels. Annals of the New York Academy of Sciences 588: 236–249.

Noden DM and Francis‐West P (2006) The differentiation and morphogenesis of craniofacial muscles. Developmental Dynamics 235: 1194–1218.

Parker HJ, Bronner ME and Krumlauf R (2016) The vertebrate Hox gene regulatory network for hindbrain segmentation: evolution and diversification: coupling of a Hox gene regulatory network to hindbrain segmentation is an ancient trait originating at the base of vertebrates. Bioessays 38: 526–538.

Pasqualetti M, Ori M, Nardi I and Rijli FM (2000) Ectopic Hoxa2 induction after neural crest migration results in homeosis of jaw elements in Xenopus. Development 127: 5367–5378.

Petryk A, Graf D and Marcucio R (2015) Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans. Wiley Interdisciplinary Reviews. Developmental Biology 4: 17–32.

Plein A, Fantin A and Ruhrberg C (2015) Neural crest cells in cardiovascular development. Current Topics in Developmental Biology 111: 183–200.

Prescott SL, Srinivasan R, Marchetto MC, et al. (2015) Enhancer divergence and cis‐regulatory evolution in the human and chimp neural crest. Cell 163: 68–83.

Ridenour DA, McLennan R, Teddy JM, et al. (2014) The neural crest cell cycle is related to phases of migration in the head. Development 141: 1095–1103.

Rijli FM, Mark M, Lakkaraju S, et al. (1993) 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.

Ruest LB and Clouthier DE (2009) Elucidating timing and function of endothelin‐A receptor signaling during craniofacial development using neural crest cell‐specific gene deletion and receptor antagonism. Developmental Biology 328: 94–108.

Ruhin B, Creuzet S, Vincent C, et al. (2003) Patterning of the hyoid cartilage depends upon signals arising from the ventral foregut endoderm. Developmental Dynamics 228: 239–246.

Sakai D, Dixon J, Achilleos A, Dixon M and Trainor PA (2016) Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation. Nature Communications 7: 10328.

Sambasivan R, Kuratani S and Tajbakhsh S (2011) An eye on the head: the development and evolution of craniofacial muscles. Development 138: 2401–2415.

Sato T, Kurihara Y, Asai R, et al. (2008) An endothelin‐1 switch specifies maxillomandibular identity. Proceedings of the National Academy of Sciences of the United States of America 105: 18806–18811.

Scarpa E, Szabo A, Bibonne A, et al. (2015) Cadherin switch during EMT in neural crest cells leads to contact inhibition of locomotion via repolarization of forces. Developmental Cell 34: 421–434.

Scarpa E and Mayor R (2016) Collective cell migration in development. Journal of Cell Biology 212: 143–155.

Schneider RA and Helms JA (2003) The cellular and molecular origins of beak morphology. Science 299: 565–568.

Schneider RA (2015) Regulation of jaw length during development, disease, and evolution. Current Topics in Developmental Biology 115: 271–298.

Schoenwolf GC, Bleyl S, Brauer PR and Francis‐West PH (2009) Larsen's Human Embryology. Philadelphia, PA: Churchill, Livingstone, Elsevier.

Sears KE, Goswami A, Flynn JJ and Niswander LA (2007) The correlated evolution of Runx2 tandem repeats, transcriptional activity, and facial length in carnivora. Evolution and Development 9: 555–565.

Shellard A and Mayor R (2016) Chemotaxis during neural crest migration. Seminars in Cell and Developmental Biology 55: 111–118.

Simoes‐Costa M and Bronner ME (2015) Establishing neural crest identity: a gene regulatory recipe. Development 142: 242–257.

Theis S, Patel K, Valasek P, et al. (2010) The occipital lateral plate mesoderm is a novel source for vertebrate neck musculature. Development 137: 2961–2971.

Theveneau E and Mayor R (2012) Neural crest migration: interplay between chemorepellents, chemoattractants, contact inhibition, epithelial‐mesenchymal transition, and collective cell migration. Wiley Interdisciplinary Reviews. Developmental Biology 1: 435–445.

Theveneau E, Steventon B, Scarpa E, et al. (2013) Chase‐and‐run between adjacent cell populations promotes directional collective migration. Nature Cell Biology 15: 763–772.

Thomas S, Thomas M, Wincker P, et al. (2008) Human neural crest cells display molecular and phenotypic hallmarks of stem cells. Human Molecular Genetics 17: 3411–3425.

Tokita M and Schneider RA (2009) Developmental origins of species‐specific muscle pattern. Developmental Biology 331: 311–325.

Treacher Collins Syndrome Collaborative Group (1996) Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. The Treacher Collins Syndrome Collaborative Group. Nature Genetics 12: 130–136.

Twigg SR and Wilkie AO (2015) A genetic‐pathophysiological framework for craniosynostosis. American Journal of Human Genetics 97: 359–377.

Valdez BC, Henning D, So RB, Dixon J and Dixon MJ (2004) The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proceedings of the National Academy of Sciences of the United States of America 101: 10709–10714.

Van Otterloo E, Williams T and Artinger KB (2016) The old and new face of craniofacial research: how animal models inform human craniofacial genetic and clinical data. Developmental Biology 415: 171–187.

Wang J, Xiao Y, Hsu CW, et al. (2016) Yap and Taz play a crucial role in neural crest‐derived craniofacial development. Development 143: 504–515.

Wu P, Jiang TX, Suksaweang S, Widelitz RB and Chuong CM (2004) Molecular shaping of the beak. Science 305: 1465–1466.

Wu P, Jiang TX, Shen JY, Widelitz RB and Chuong CM (2006) Morphoregulation of avian beaks: comparative mapping of growth zone activities and morphological evolution. Developmental Dynamics 235: 1400–1412.

Yoshida T, Vivatbutsiri P, Morriss‐Kay G, Saga Y and Iseki S (2008) Cell lineage in mammalian craniofacial mesenchyme. Mechanisms of Development 125: 797–808.

Yu JK, Meulemans D, McKeown SJ and Bronner‐Fraser M (2008) Insights from the amphioxus genome on the origin of vertebrate neural crest. Genome Research 18: 1127–1132.

Zhang D, Ighaniyan S, Stathopoulos L, et al. (2014) The neural crest: a versatile organ system. Birth Defects Research. Part C, Embryo Today 102: 275–298.

Zhao H and Chai Y (2015) Stem cells in teeth and craniofacial bones. Journal of Dental Research 94: 1495–1501.

Zhao H, Feng J, Ho TV, et al. (2015) The suture provides a niche for mesenchymal stem cells of craniofacial bones. Nature Cell Biology 17: 386–396.

Further Reading

Bhatt S, Diaz R and Trainor PA (2013) Signals and switches in Mammalian neural crest cell differentiation. Cold Spring Harbor Perspectives in Biology 5. pii: a008326.

Dixon MJ, Marazita ML, Beaty TH and Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews. Genetics 12: 167–178.

Green SA, Simoes‐Costa M and Bronner ME (2015) Evolution of vertebrates as viewed from the crest. Nature 520: 474–482.

Mayor R and Theveneau E (2013) The neural crest. Development 140: 2247–2251.

Michailovici I, Eigler T and Tzahor E (2015) Craniofacial muscle development. Current Topics in Developmental Biology 115: 3–30.

Minoux M and Rijli FM (2010) Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137: 2605–2621.

Schoenwolf GC, Bleyl S, Brauer PR and Francis‐West PH (2009) Larsen's Human Embryology. Philadephia, PA: Churchill, Livingstone, Elsevier.

Twigg SR and Wilkie AO (2015) A genetic‐pathophysiological framework for craniosynostosis. American Journal of Human Genetics 97: 359–377.

Zhao H and Chai Y (2015) Stem cells in teeth and craniofacial bones. Journal of Dental Research 94: 1495–1501.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Francis‐West, Philippa, and Crespo‐Enriquez, Ivan(Dec 2016) Vertebrate Embryo: Craniofacial Development. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026602]