Craniosynostoses refer to the premature fusion of one or more cranial sutures. The skull develops from several ossification centers that give rise to membranous flat bones; these meet at fibrous junctions, the sutures, whose role is to maintain a separation between the bones while allowing the harmonious deformation of the skull during brain growth. When this separation fails, a bony bridge forms between two bones and causes the early fusion of the suture. Syndromic forms are frequently linked to point mutations in specific genes, foremost among which are the FGFR1, FGFR2, and FGFR3 receptors as well as the TWIST gene. This literature review surveys the animal models developed for these conditions and analyzes their contribution to the understanding of normal and pathological craniofacial growth.
Two species stand out. The mouse and the zebrafish possess a largely sequenced genome that is highly similar to the human genome, as well as a cranial vault whose organization is analogous to that of humans, despite differences in cell identity and timing during organogenesis. Genetic tools allow these two genomes to be manipulated with precision in order to delete, add, or replace sequences and thereby modulate gene expression and function. The authors emphasize that CRISPR/Cas9 technology, which directs the Cas9 endonuclease to targeted genomic sites using guide RNAs, now makes it possible to produce knock-out and knock-in mutants in zebrafish, which will facilitate the testing of candidate alleles and the dynamic study of their impact on skull formation.
Many mouse models have been generated for the most common syndromic craniosynostoses. The review details in particular models reproducing Pfeiffer (Fgfr1 P250R), Apert (Fgfr2 S252W and P253R), Crouzon (Fgfr2 C342Y and W290R), Beare-Stevenson (Fgfr2 Y394C), and Muenke (Fgfr3 P244R) syndromes, associated with characteristic phenotypes: dome-shaped skull, midface hypoplasia, hypertelorism, malocclusion, and skull base abnormalities. Other genes are also implicated, including MSX2, EFNA, GLI3, FREM1, and FGF3/4. The zebrafish, although less studied, proves useful for exploring the mechanisms of suture formation conserved across vertebrates; work on retinoic acid, for example, has shown that a fragmented cranial vault results from premature differentiation of osteoblasts into preosteocytes and the subsequent activation of osteoclasts.
These models have enriched the understanding of craniofacial growth and have also been used to test pharmacological treatments aimed at restoring this growth. As the current treatment of craniosynostoses is almost exclusively surgical, with associated morbidity and mortality and the need for repeated interventions in syndromic forms, pharmacological approaches represent a therapeutic alternative. In this respect, mouse models reproducing craniosynostoses can be readily mobilized for the screening of candidate molecules.
This publication benefited from the expertise of Inovarion.