The Mechanism Of FGF And BMP Signaling Pathway In Mammalian Tooth And Palate Development

The normal development of craniofacial organs is the guarantee of one's daily life.Teeth and palate are two major organs in craniofacial region.Multiple signaling molecule families,including Bone morphogenetic protein(BMP),fibroblast growth factor(FGF),Hedgehog(Hh)and Wnt,are implicated in tooth and palate development.In the study,we investigate the mechanism of FGF and BMP signaling in tooth and pallate.Human and mouse exhibite great diversity in tooth development rate.In the present study,we conducted tissue recombination of human and mouse dental component,and found that differentiation of mouse dental epithelium was significantly delayed after induction of the human dental mesenchyme.FGF signaling was involved in tooth development rate through examination of several signaling related markers.We further utilized a transgenic mouse model and found that FGF8 plays a critical role in regulating tooth development rate and size,resulting delayed tooth development and enlarged tooth size.Constructed Wntl-Cre;pMes-Fgf9 transgenic mice also showed delay of tooth development.Further study the mechanism of tooth development in Wntl-Cre;Rosa-Fgf8 transgenic mice,we concluded that enhanced Fgf8 signaling is mainly mediated by P38 MAPK intracellular pathway to promote the transition of the cell cycle from G1 to S-phase,resulting in the stimulation of cell proliferation and inhibition;of cell differentiation and apoptosis,thus resulting in prolonged tooth development rate and enlarged tooth size.We then conducted the study of other craniofecial organs using Wntl-Cre;pMes-Fgf9 transgenic mice.Our results showed that a series of craniofecial abnormalities was shown in Wnt1-Cre;pMes-Fgf9 transgenic mice,including micrognathia,abnormal tongue,and cleft palate,resembling human Pierre-Robin syndrome.Deeply investigate of the mechanism revealed that the cleft palate in Wntl-Cre;pMes-Fgf9 mice was caused by a deformed raised tongue which is the result of micrognathia,similar to human Pierre-Robin syndrome.BMP signaling plays crucial role in tooth development,which could regulate MSX1 expression during odontogenesis.The expression of MSX1 is generally consided to regulated by BMP canonical pathway.While it has been reported that deletion of Smad4 in dental mesenchyme have no effect in tooth development,showing that BMP canonical pathway is not involed in the process.Our previous study have shown that an atypical canonical BMP signaling pathway regulates Msx1 expression during mouse odontogenesis.However,it remained elusive as to which signaling pathway BMP regulates MSX1 in the developing human tooth germ..In the present investigation,we showed that BMP signal regulate the expression of MSX1 is Smad1/5/8-dependent.Further examination of the classical BMP signaling pathway in human mesenchymal cells revealed that pSMAD1/5/8 nuclear translocation was independent of SMAD4.SMAD4 was not required for the expression of MSX1.It was also confirmed in immortalized human dental pulp stem cells.Our results demonstrate that an identically atypical canonical BMP signaling(Smad4-independent and Smadl/5/8-dependent)pathway was involved in the human dental mesenchyme.In the study,we study the mechanism of FGF signaling pathway in regulation of tooth development rate and size,the function of FGF signaling in palatogenesis,and the BMP signaling pathway in human dental mesenchyme.The result provide the prerequisite information for further understanding the molecular mechanisms of human tooth and palate development.Our result will provide theoretical principle for further implication of human tooth regeneration and revealing the genetic machnism of cleft palate.