Cranial Neural Crest Cells and Their Role in the Pathogenesis of Craniofacial Anomalies and Coronal Craniosynostosis

Abstract

Craniofacial anomalies are among the most common of birth defects. The pathogenesis of craniofacial anomalies frequently involves defects in the migration, proliferation, and fate of neural crest cells destined for the craniofacial skeleton. Genetic mutations causing deficient cranial neural crest migration and proliferation can result in Treacher Collins syndrome, Pierre Robin sequence, and cleft palate. Defects in post-migratory neural crest cells can result in pre- or post-ossification defects in the developing craniofacial skeleton and craniosynostosis (premature fusion of cranial bones/cranial sutures). The coronal suture is the most frequently fused suture in craniosynostosis syndromes. It exists as a biological boundary between the neural crest-derived frontal bone and paraxial mesoderm-derived parietal bone. The objective of this review is to frame our current understanding of neural crest cells in craniofacial development, craniofacial anomalies, and the pathogenesis of coronal craniosynostosis. We will also discuss novel approaches for advancing our knowledge and developing prevention and/or treatment strategies for craniofacial tissue regeneration and craniosynostosis.

Keywords: craniofacial; craniofacial abnormalities; craniosynostoses; growth and development; neural crest; skull.

Figure 1

Early neural crest cell development in mouse embryos. (a) Gastrulation: neural crest cells are induced at the neural plate border (NPB) between the neural plate (NP) and non-neural ectoderm (E). Paraxial mesoderm (PM) is underlying. (b) Neurulation: the neural crest becomes specified. The neural plate begins to fold to later form the neural tube (NT). (c) Prior to neural tube closure in mouse, epithelial-mesenchymal transition (EMT) triggers neural crest cells to delaminate from the neural tube and migrate throughout the embryo. Migratory neural crest cells express Sox10.

Figure 2

Coronal craniosynostosis influences skull growth and shape in humans. During late embryonic and early postnatal development, the skull increases in size via osteogenesis within the osteogenic fronts of each cranial bone. With no fusion of cranial sutures, the skull increases in size and maintains a normocephalic shape. Coronal, sagittal and lambdoid sutures remain patent, while the metopic suture fuses within months after birth (a,c). Upon coronal suture fusion, the anterior aspect of the parietal bone(s) fuses with the posterior aspect of the frontal bone(s) such that growth cannot occur in this region. This leads to an acrocephalic (taller relative to anterior-posterior length) (b) and brachycephalic (wider relative to anterior-posterior length) skull shape (d). Limited growth along the coronal suture also leads to compensating vertical and transverse overgrowth along other non-fused sutures, such as the sagittal and lambdoid sutures. Limited skull growth due to craniosynostosis causes high intracranial pressure which must be surgically relieved. sag = sagittal suture, cor = coronal suture, lam = lambdoid suture, met = metopic suture, O = occipital bone, P = parietal bone, F = frontal bone, T = temporal bone, M = maxillary bone. Bone and suture labels in blue are derived from paraxial mesoderm. Bone and suture labels in red are derived from cranial neural crest. Note: all facial bones and sutures are derived from neural crest.

Figure 3

Embryonic Development of the Coronal Suture with Frontal and Parietal Bones. The coronal suture exists as a physical boundary separating the neural crest-derived frontal bone and paraxial mesoderm-derived parietal bone throughout embryonic development. (a–e) Schematics depict lateral view of whole skull. (c’–e’) Schematics depict sagittal sections of the skull lateral to the midline to describe the spatial relationship of the developing frontal and parietal bones. The expression patterns of genes essential for development are depicted in various colors at indicated time points.

Figure 4

Postnatal Delivery of Tissue Nonspecific Alkaline Phosphatase (TNAP) Enzyme Diminishes Abnormal Craniofacial Phenotype of Crouzon Fgfr2^C342Y/+ Mice. (a) Percentage of vehicle (control) and TNAP treated Fgfr2^C342Y/+ mice with a class III malocclusion are shown. Results show a significantly decreased incidence of malocclusion in C57BL/6 Fgfr2^C342Y/+ mice. (b) Percentage of vehicle (control) and TNAP treated Fgfr2^C342Y/+ mice with coronal suture fusion are shown. Fusion was scored as: (1) diminished suture width with no fusion, (2) diminished suture width with point fusions across the suture, and (3) obliteration of the suture. Results show a significantly decreased incidence of suture obliteration in C57BL/6 Fgfr2^C342Y/+ mice. * p < 0.03 between treatment groups. (c,c’) Axial and lateral isosurface images of Alpl^−/− (TNAP knockout) mice exhibit craniofacial bone hypomineralization that is more severe in bone of cranial neural crest than paraxial mesoderm origin. Note that numerous bones of neural crest origin are so hypomineralized that they do not appear on a micro CT image generated using a bone threshold. Adapted from [203].