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Shaping faces: genetic and epigenetic control of craniofacial morphogenesis

Nature Reviews Genetics volume 24, pages 610–626 (2023)Cite this article

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Abstract

Major differences in facial morphology distinguish vertebrate species. Variation of facial traits underlies the uniqueness of human individuals, and abnormal craniofacial morphogenesis during development leads to birth defects that significantly affect quality of life. Studies during the past 40 years have advanced our understanding of the molecular mechanisms that establish facial form during development, highlighting the crucial roles in this process of a multipotent cell type known as the cranial neural crest cell. In this Review, we discuss recent advances in multi-omics and single-cell technologies that enable genes, transcriptional regulatory networks and epigenetic landscapes to be closely linked to the establishment of facial patterning and its variation, with an emphasis on normal and abnormal craniofacial morphogenesis. Advancing our knowledge of these processes will support important developments in tissue engineering, as well as the repair and reconstruction of the abnormal craniofacial complex.

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Fig. 1: Facial development in humans and mice.
Fig. 2: Genetic regulation of cranial neural crest cells and conservation of homeodomain gene function.
Fig. 3: Identification of multilayered gene regulatory networks in cranial neural crest cells using multi-omics approaches.
Fig. 4: Epigenetic regulation of the positional plasticity and identity of cranial neural crest cells.
Fig. 5: Loss of long-range enhancers in human cranial neural crest cells results in Pierre Robin sequence, a congenital craniofacial disorder.

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Acknowledgements

The authors thank R. Aho for the original preparation of all artwork, N. Tian for generating the library of references, P. Martin for editing the manuscript, G. Panagiotakos for discussions and input, and E. Nora, D. Wagner and S. Weinberg for comments on select sections of the Review. The authors received funding from the NIH (R01 DE024745, R01 DE028324, R01 DE028753, U01 DE024430 FaceBase2) and the March of Dimes and Birth Defects Foundation to L.S.; and from the Swiss National Science Foundation (CRSII5_173868), the European Research Council under the European Union’s Horizon 2020 research and innovation programme (810111-EpiCrest2Reg) and the Novartis Research Foundation to F.M.R.

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Authors and Affiliations

  1. Program in Craniofacial Biology, Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco, CA, USA

    Licia Selleri

  2. Department of Anatomy, School of Medicine, University of California, San Francisco, CA, USA

    Licia Selleri

  3. Laboratory of Developmental Neuroepigenetics, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    Filippo M. Rijli

  4. University of Basel, Basel, Switzerland

    Filippo M. Rijli

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  1. Licia Selleri
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Glossary

Branchial arches

Also known as pharyngeal arches. Segmented structures arising as a series of endodermal outpockets on the sides of the developing pharynx that are filled with ectomesenchymal cells derived from cranial neural crest and mesodermal cells. They give rise to multiple facial and visceral structures, including skeletal, muscular and neural elements.

Branchio-oto-renal syndrome

This syndrome is characterized by neck and external ear abnormalities, including hearing loss, and kidney defects. Symptom severity varies greatly from person to person.

Collinear

Refers to the physical gene order within each Hox cluster on the chromosome (telomeric to centromeric), which correlates with the serial activation of these genes along the anterior–posterior embryonic body axis.

Epithelial-to-mesenchymal transition

(EMT). Process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal cells.

Frontonasal prominence

(FNP). Midline, unpaired embryonic structure that develops between the telencephalon, the forming oral cavity and the nasal pits, into the forehead.

Homeodomain

The DNA-binding homeobox domain (homeodomain) is encoded by a 180-bp homeobox DNA sequence, found within genes encoding transcription factors that are involved in pattern formation during development in animals, fungi, plants and numerous single-cell eukaryotes.

Homeotic transformation

Morphological variation in body plan in which one structure is changed into the likeness of another structure, arising from loss-of-function or gain-of-function mutations of the developmentally crucial homeotic genes.

Hox genes

Also known as homeotic genes. A subset of homeodomain genes that specify the morphology of the distinct structures of the body plan of an embryo along the anterior–posterior (head-to-tail) body axis. Mammals have 39 Hox genes, organized into four clusters of 9–11 paralogous genes (some clusters lack select paralogues), resulting from successive evolutionary duplications.

Hyoid bone

Horseshoe-shaped bone situated in the anterior midline of the neck between the base of the lower jaw and the thyroid cartilage that provides an attachment structure for the tongue. The greater horns of the hyoid bone arise from branchial arch 3, whereas the lesser horns originate from branchial arch 2.

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells that can be generated directly from a somatic cell by the introduction of specific transcription factor genes (MYC, OCT3, OCT4, SOX2 and KLF4).

Lateral nasal prominence

(LNP). Ectoderm-covered swelling filled with mesenchymal cells of cranial neural crest origin that separates the embryonic olfactory pit from the developing eye. The wings of the nose (alae nasi) develop from the LNP.

Mandibular prominences

(MdPs). Caudal prominences formed by bifurcation of embryonic branchial arch 1. Each MdP fuses antero-ventrally with the MdP on the other side of the embryonic face to form the lower jaw.

Maxillary prominence

(MxP). Rostral prominence formed by bifurcation of embryonic branchial arch 1, which joins with the ipsilateral medial nasal prominence to form the upper jaw.

Meckel’s cartilage

Bilaterally paired, rod-like, cartilaginous ventral component of the lower jaw, within the branchial arch 1-derived mandibular prominences of vertebrate embryos.

Medial nasal prominence

(MNP). Ectoderm-covered swelling filled with mesenchymal cells of cranial neural crest origin that lies medial to the olfactory pit in the embryo. The nasal tip and philtrum (midline groove) of the lip (in humans) develop from the MNP.

Middle ear ossicles

The incus, malleus and stapes, which transfer vibrations from the eardrum to the inner ear. The incus and malleus are derived from branchial arch 1, whereas the stapes is derived from branchial arch 2.

Multi-omics

Branch of biological science comprising various experimental approaches, such as genomics, transcriptomics, proteomics, metabolomics and phenomics. The goal of multi-omics is the combined characterization and quantification of large data sets that translate into the structure and function of an organism.

Neurocristopathies

A class of human disorders that result from abnormal expression, migration, differentiation or death of neural crest cells during embryonic development.

Paralogous

Genes related to each other through a gene duplication event. A paralogous gene in the same organism gains novel regulation and function, but also often keeps redundant functions with its paralogues. An example of paralogous genes is provided by genes in similar linear positions in the distinct Hox clusters.

Rhombomere 4

The rhombomeres (up to eight in total) are transient compartments of neuroepithelial precursor cells formed in the developing hindbrain of vertebrate embryos. They appear as a series of swellings with meristic organization in the early developing neural tube.

Stomodeum

The primitive oral cavity, which forms between the frontonasal process and branchial arch 1.

Topologically associating domain

(TAD). Self-interacting genomic region of approximately 1 Mb. DNA sequences within a TAD are likely to interact physically with each other more frequently than with sequences outside the TAD.

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Selleri, L., Rijli, F.M. Shaping faces: genetic and epigenetic control of craniofacial morphogenesis. Nat Rev Genet 24, 610–626 (2023). https://doi.org/10.1038/s41576-023-00594-w

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