Developmental basis of natural tooth shape variation in cichlid fishes.

While most dentate non-mammalian vertebrates possess simple conical teeth, some demonstrate complex tooth shapes. Lake Malawi cichlid fishes are an extreme example of this, exhibiting a myriad of tooth shapes driven by an ecologically derived rapid evolution of closely related but distinct species. Tooth shape in mammals is generally considered to be established by signaling centers called primary and secondary enamel knots, which are not believed to be present in non-mammalian vertebrates. In this study, signaling centers of gene expression with epithelial folding with similar molecular patterns to that of mammalian enamel knots are identified, and differences of asymmetric gene expression are identified between fish that possess species specific polymorphisms of either bicuspid or tricuspid teeth. Gene expression is then manipulated indirectly using a small molecule inhibitor of the Notch pathway, resulting in phenotypical aberrations of tooth shape and patterning, including a mimic of a tricuspid tooth in a fish with a naturally occurring bicuspid dentition. This study provides insight into the evolutionary origins of tooth shape and advances our knowledge of the molecular determinants of dental morphology with translational utility in regenerative dentistry.