Abstract
Syngnathia (bony fusion of the upper and lower jaw) is a rare human congenital condition, with fewer than sixty cases reported in the literature. Syngnathia typically presents as part of a complex syndrome comprising widespread oral and maxillofacial anomalies, but it can also occur in isolation. Most cartilage, bone, and connective tissue of the head and face is derived from neural crest cells. Hence, congenital craniofacial anomalies are often attributed to defects in neural crest cell formation, survival, migration, or differentiation. The etiology and pathogenesis of syngnathia however remains unknown. Here, we report that Foxc1 null embryos display bony syngnathia together with defects in maxillary and mandibular structures, and agenesis of the temporomandibular joint (TMJ). In the absence of Foxc1, neural crest cell derived osteogenic patterning is affected, as osteoblasts develop ectopically in the maxillary prominence and fuse with the dentary bone. Furthermore, we observed that the craniofacial musculature is also perturbed in Foxc1 null mice, which highlights the complex tissue interactions required for proper jaw development. We present evidence that Foxc1 and Fgf8 genetically interact and that Fgf8 dosage is associated with variation in the syngnathic phenotype. Together our data demonstrates that Foxc1 – Fgf8 signaling regulates mammalian jaw patterning and provides a mechanistic basis for the pathogenesis of syngnathia. Furthermore, our work provides a framework for understanding jaw patterning and the etiology of other congenital craniofacial anomalies, including temporomandibular joint agenesis.
Highlights
Jawed vertebrates, or gnathostomes, represent the majority of extant vertebrate species
We discovered that Foxc12/2 mutant mice exhibit a bilateral fusion of the upper jaw zygomatic complex to the dentary bone (Figure 2A, B) closely mimicking a condition in humans termed syngnathia
Fusion occured either proximal to the molar alveolar ridge (n = 7/13, Figure 2D) or encompassed the entire alveolar region (n = 6/13, Table 1). This phenotype has been previously described as an enlarged zygomatic process of the maxilla [26] or as massively ossified zygomatic and dentary bones [27], our more detailed analyses indicate that Foxc12/2 mutant mice represent a unique previously undescribed model for studying the pathogenesis of syngnathia
Summary
Gnathostomes, represent the majority of extant vertebrate species. The vertebrate jaw consists of separate upper and lower skeletal elements connected by a joint. The first pharyngeal arch can be subdivided into discrete upper (maxillary) and lower (mandibular) portions, which contribute to the upper and lower jaw respectively. In addition to these cell populations, the medial (MNP) and lateral (LNP) nasal prominences make key tissue and signaling contributions to jaw development [14,15,16,17,18]. The jaw is constructed from several distinct and separate skeletal elements derived from these prominences including the maxilla, jugal, squamosal, and dentary bones. The TMJ is a complex synovial joint and consists of the glenoid fossa of the squamosal bone, the condylar head of the dentary, a fibrocartilaginous disc that is located between these two bones, and muscles and tendons that attach to the joint [19]
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