Fgf8 dosage regulates jaw shape and symmetry through pharyngeal-cardiac tissue relationships

BackgroundAsymmetries in craniofacial anomalies are commonly observed. With respect to the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. ResultsDevelopmental reductions in Fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with an early disruption to Meckels cartilage, which is discontinuous and appears as two separate condensations in Fgf8 mutants. All skeletal elements associated with the proximal condensation are dysmorphic in the mutants, which is exemplified by a malformed and mis-oriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into 2 broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-individual variation. ConclusionsWe hypothesize that these asymmetries are linked to asymmetries in heart development resulting in higher levels of Fgf8 on the right side of the face during development, which may buffer the right side to mild developmental perturbations. This mutant mouse is a good model for future investigations of mechanisms underlying human syngnathia and facial asymmetry.