The Role Of BMP Signaling In Early Development And Attachment Of Maxillofacial Muscles And The Role Of FGF Signaling In Early Development Of The Temporomandibular Joint

Craniofacial malformations account for at least one-third of all congenital defects,many of which are classified as CNCCs(cranial neural crest cells)related diseases.These CNCCs related diseases are thought to be involved with abnormalities in the formation,distribution,proliferation,and differentiation of CNCCs,and with interactions between CNCCs and other craniofacial tissues.Focusing on the effects of BMP signaling on early development of maxillofacial muscles and the establishment of muscle attachment,we explained the physiological and pathological effects of CNCCs-derived BMP4 signaling in maxillofacial muscle development through the study of Wnt1-Cre;pMes-Bmp4 and Wnt1-Cre;Bmp4^fl/flmouse models.Focusing on the effects of FGF signaling on the early development of the temporomandibular joint condylar cartilage,we affirmed the effects of the FGF signaling on the bi-potential and maturation rate of the condyle through the study of Wnt1-Cre;pMes-Fgf9 and Wnt1-Cre;pMes-Fgf18mouse models.Wnt1-Cre;pMes-Bmp4 mice have a deformity similar to a rare congenital defect in humans-congenital bone fusion.In this pathological model of Wnt1-Cre;pMes-Bmp4,we found that overexpression of Bmp4 in CNCCs causes secondary cartilage loss and tendon dysplasia through autonomous effects,and causes abnormal proliferation and differentiation of maxillofacial muscles through non-autonomous effects..Our study partially explained the role of BMP4 signaling in the development of maxillofacial region,and explained the pathology of combined craniofacial congenital malformation.Wnt1-Cre;Bmp4^fl/flmouseisan appropriate model for investigating the physiological role of BMP4 signaling in the development of maxillofacial region.We found that Wnt1-Cre;Bmp4^fl/fl mice show abnormal attachment of the genioglossus,and thatthe cause of muscle attachment abnormalities lies in the loss of the Meckel cartilage's rostral process.The cartilage defect is partly related to the proliferation disorder of chondrocytes.For the first time,we discovered the unique regulation of the Meckel cartilage front by the BMP4signal from the CNCCs.In addition,BMP4 knockout in CNCCs cause obstacles in maxillofacial muscle differentiation and increased proliferation in mesenchyme,which are correspondingly associated with a decrease of classical BMP signaling in muscle and an increase of P38-mediated non-classical BMP signaling in mesenchyme.We deduce that the mechanism of cleft palate in Wnt1-Cre;Bmp4^fl/fl mice is associated with abnormal attachment of the genioglossus,and that the pathological mechanism is consistent with the Pierre Robin sequence.We selected Wnt1-Cre;pMes-Fgf9 mice as a model to investigate the role of CNCCs-derived FGF9 in the early development of condyle.In this mice model,We found a series of disorders in cartilage-determining,proliferating,differentiating,and maturation.The occurrence of disorders of proliferation and differentiation are associated with inactivation of FGF signaling.An important finding in our study is that the CNCCs-derived FGF9 signal is associated with the bi-potential of the condyle.Overexpression of FGF9 simultaneously impair the two-way differentiation of the condylar cells.Wnt1-Cre;pMes-Fgf18 mice are a model for further investigation of the effects of CNCCs-derived FGF signaling on the early development of condyles.The condylar disorder mainly display in the late stage of cartilage morphogenesis.Condylar chondrocytes lose multi-layered cellular structure,and hypertrophy of chondrocytes fail to appear.We thus confirmed that FGF18 has a regulatory effect on the rate of condyle maturation.Wnt1-Cre;pMes-Fgf9 mice and Wnt1-Cre;pMes-Fgf18 mice similarly show abnormalities in the osteogenesis of the membrane bone,and overexpression of FGF signals in the CNCCs can cause significant advancement of the bone differentiation,which can explain the the cranial congenital malformation phenotypes associated with FGF signaling overactivation.In addition,we first demonstrated the temporal and spatial pattern of the classical BMP signal in the early development of maxillofacial muscles,and discovered a layer of mesodermal cells located at the surface of the condyle.These findings provide a new perspective for studying the early development of maxillofacial muscles and the temporomandibular joint,and may contribute to expanded understanding of developmental patterns.