Bmp4/p38信号对小鼠上下颌磨牙模式形成的调控作用

研究模式形成对理解器官发生具有重要意义。关于小鼠磨牙模式形成，现仅知在牙齿发育早期，每侧上颌和下颌中各仅有一个磨牙牙胚（起源同侧的第一鳃弓），但关于这些上下颌磨牙牙胚究竟如何从第一鳃弓中形成仍一无所知。我们前期构建的Wnt1-Cre;pMes-Bmp4小鼠模型表现出磨牙模式形成异常表型：每侧颅颌面仅在上下颌连接处长有一个磨牙牙胚。进一步研究表明，小鼠每侧上下颌的磨牙牙胚是由该侧第一鳃弓中的同一预定磨牙原基随第一鳃弓形成上颌突的过程中，一分为二形成的。颅神经嵴细胞中Bmp4/p38信号的异常提高改变了该模式化过程中调控细胞迁移相关基因的表达，从而导致磨牙原基分裂失败。将利用构建的小鼠模型，采用遗传学、基因组学及生物信息学等技术，在基因转录及表观遗传调控水平解析Bmp4/p38信号对小鼠上下颌磨牙模式形成的调控作用，对理解颅颌面其他器官模式形成和人类先天性牙齿发育不全发病机理也将有重要的启迪。

Pattern formation is the fundamental principle for understanding organogenesis. For molar pattern formation, it is only known that there is only one molar germ in each side of the maxillary and mandibular jaw originating from the homolateral first branchial arch during early tooth development. However, how the unilateral maxillary and mandibular molar germ are generated from the first branchial arch remains unknown. Our preliminary mouse model (Wnt1-Cre;pMes-Bmp4) exhibits an abnormal phenotype of pattern formation that only one molar germ exists at the junction of the unilateral maxillary and mandibular jaw. Further studies present evidence that the homolateral maxillary and mandibular molar are generated by the same presumptive molar primordium in the homolateral first branchial arch which splits into two molar germs as the first branchial arch extends upwards to form the maxillary prominence. The abnormal elevated Bmp4/p38 signal in cranial crest cells of Wnt1-Cre;pMes-Bmp4 mice changes the expression of critical genes involved in cell migration of patterning, thus resulting in the splitting failure of presumptive molar primordium. In this application, we will utilize Wnt1-Cre;pMes-Bmp4 mouse model and employ genetics, molecular biology, genomics, and bioinformatics approaches to explore the regulatory effect of Bmp4/p38 signal on the patterning of the maxillae-mandibular molar in mice. The results obtained will provide novel knowledge for understanding the molecular patterning of molar as well as other maxillofacial organs and the pathomechanism of congenital tooth agenesis in humans.