Disrupted early molar patterning in syngnathia mouse model

It is well established that tooth morphogenesis initiates at embryonic day 11.5 (E11.5), characterized by the specification of a single molar germ in each jaw quadrant. However, the developmental mechanisms establishing the spatially distinct maxillary and mandibular identities along the jaw axis prior to this stage remain elusive. In Wnt1-Cre;pMes-Bmp4 transgenic mice, a pathological model recapitulating human syngnathia (resulting in bilateral jaw fusion), we demonstrate here that BMP4 overexpression in cranial neural crest cells (CNCC) disrupts early molar patterning with 100% penetrance, manifesting as the formation of only one molar germ within each unilateral fused jaw structure, establishing this model as a valuable tool for investigating the patterning of maxillary and mandibular molar germs during jaw development. Systematic analysis of wild-type embryos revealed the emergence of a single molar primordium in the unilateral first pharyngeal arch (PA1) by E9.0. This primordium undergoes segregation to form the maxillary and mandibular molar germs between E9.5 and E9.75, a process synchronized with the anteroposterior patterning of PA1. Comparative studies with the mutant model indicated that this developmental segregation depends on coordinated migration of CNCC-derived molar primordium and a BMP4/FGF8-dependent gene regulatory network (GRN) at the maxillomandibular junction. Pathologically elevated BMP4 signaling upregulates the p38 intracellular pathway in the mutant jaws, perturbing the finely tuned GRN and disrupting post-migratory CNCC migration. These perturbations collectively lead to defective molar segregation in the syngnathia mouse model. Our findings elucidate fundamental mechanisms governing early molar patterning and may provide molecular explanations for syngnathia-associated molar oligodontia in humans.