BMP And FGF Signaling In Mammalian Tooth Development

Multiple families of signaling molecules, including Fibroblast Growth Factors (FGFs), Bone Morphogenetic Proteins (BMPs), Wnt, and Hedgehog (Hh), are implicated in mediating tissue interactions that govern every step of mammalian organogenesis. The developing mouse tooth is an excellent model to study fundamental processes and mechanisms of vertebrate organogenesis, including induction, differentiation, and pattern formation. While recent studies have begun to reveal molecular mechanisms of tooth development in mice, little is known about the genetic control of tooth development in humans. The current study focuses on the expression and functional mechanism of BMP and FGF signaling in tooth development in both humans and mice.We began with the examination of the expression patterns of BMP and FGF signaling components in the developing human tooth germs by in situ hybridization, and compared them with those in mice. We found strong expression of BMP ligands, receptors, effectors, and antagonist, including BMP2, BMP3, BMP4, BMP7, NOGGIN, SMAD4, BMPRIa, BMPRIb, and BMPRII, in the developing human tooth germ at the cap and bell stages. Strong expression of FGFs ligands and their receptors, including FGF3, FGF4, FGF7, FGF8, FGF9, FGF10, FGFR1and FGFR2, were also found in the developing human tooth germs. Our results showed that these genes exhibit overlapping but slightly different expression patterns as compared with their counterparts in the developing mouse tooth germ both at the stages examined, suggesting conserved and distinct roles of BMP and FGF signaling pathways in human tooth development. Despite striking similarities in morphology and pattern in the odontogenesis between the mouse and the human, species-specific genetic regulatory mechanisms are still unknown. Our results provide a fundamental base for further studies on the role of BMP and FGF signaling in modulating human tooth development.Signaling homeostasis plays crucial roles in the development of many organs. We used a genetically modified mouse model, the Noggin mutant mouse, to investigate the functional importance of BMP homeostasis in tooth morphogenesis. Our studies showed that Noggin is a key molecule for the upper incisors development. The absence of Noggin leads to the fusion of the upper incisor placode due to overactive BMP activity. However, the molars and lower incisor formed normally. We found that Chordin and Gremlin, another two BMP antagonists, were co-expressed with Noggin in the developing lower incisor and molar teeth, suggesting a functional redundancy between these BMPs antagonists during tooth development.The average length of time for human tooth development, from the initiation to eruption, is about400days. However, this process in mice only takes20days. This is a major noticeable difference in tooth development between humans and mice. We have found that FGF8exhibits a different expression pattern between humans and mice, being expressed in both dental epithelium and mesenchyme throughout the tooth development stages in humans, in contrast to its transient expression in the dental epithelium at the earlier stage in mice. Lentivirus-mediated overexpression of Fg/8in the dental mesenchyme of mouse E13.5molar tooth germ led to delayed tooth development and differentiation in subrenal culture. Tissue recombination of the mouse bud stage dental epithelium (E13.5) with the human early bell stage dental mesenchyme (14-week gestation) produced a mouse-human chimeric tooth crown, with significantly delayed mouse ameloblast differentiation. In the reciprocal tissue recombination experiments, when the human early bell stage dental epithelium (14-week gestation) were combined with the mouse bud stage dental mesenchyme (E13.5), human-mouse chimeric tooth crown formed with accelerated differentiation of the human dental epithelium. Our results suggest that Fgf8plays a critical role in regulating the rate of tooth development and differentiation.In sum, in this study, we first examined the expression patterns of BMP and FGF signaling components in the developing human tooth germ. The results provide prerequisite information for further understanding the molecular mechanisms of these signaling pathways in human tooth development. Secondly, we used genetically modified mouse model to validate functional importance of BMP signaling homeostasis in tooth development. Lastly, we showed that FGF8plays a key role in the regulation of tooth development rate. Our results will have great implication in the generation of bioengineered teeth for the future tooth replacement therapy in humans.