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

Background Asymmetries in craniofacial anomalies are commonly observed. In 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. Results Developmental 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 disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two 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‐specimen variation. Conclusions We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry. Key Findings Reductions in Fgf8 have dosage‐dependent effects on proximal jaw and middle ear morphology Defects in lower jaw development in Fgf8 mutants are directionally asymmetric, with the left side being more affected than the right Fgf8 mutants exhibit the two types of syngnathia observed in humans: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico‐mandibular fusion Morphogenesis of pharyngeal epithelia is disrupted in Fgf8 mutants, causing further disruptions to gene expression in the pharyngeal arches Asymmetry in jaw defects is associated with asymmetry in Fgf8 expression in the developing heart