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, Tcof1 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 Msx1, Barx1 and Dlx5/6 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 Dlx5/Dlx6 or Endothelin‐1, which regulates Dlx5/6 expression, transforms the mandibular primordia to the maxillary primordia. (d) Conversely gain of ENDOTHELIN‐1 signalling (which induces Dlx5/6 expression) or the expression of Hand2, a transcriptional mediator of Dlx5/6 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 and pasteexperiments 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. () © 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 FGFR1,2 or 3 or increased expression/activity of RUNX2 (e.g. increased copies of Runx2), 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.


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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.

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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]