Mechanisms of FoxJ1 Tooth Morphogenesis

描述(申请人提供)：近年来，一些新的基因被鉴定出来，它们与牙齿形态发生有关。尽管在识别新的基因和调控牙齿发育的形态发生阶段的信号机制方面已经取得了很大进展，但调控成牙本质细胞和成釉细胞分化的转录机制却知之甚少。更好地了解这一过程的机制是必要的，这不仅是为了了解正常的牙齿形态发生，也是为了再生牙齿，并最终能够开发和提供更好的治疗策略。我们实验室已经发现FoxJ1是一个新的转录因子，参与牙齿和颅面的晚期形态发生。FoxJ1(又称HfH-4、FHKL-13)属于叉头基因家族，含有一个叉头(也称为翼状螺旋)DNA结合域，通过决定细胞命运来调节发育。我们的初步数据显示，FoxJ1从E18.5开始在小鼠磨牙内牙上皮细胞中表达，在新生第1天的成釉细胞和成牙本质细胞中表达，在E17.5和新生第1天的口腔上皮和下颌下唾液腺中也有表达。我们的瞬时转染数据表明，FoxJ1被PITX2激活，并与PITX2物理上相互作用。PITX2是参与颅面/牙齿早期发育的同源框转录因子基因。这项建议的总体目标是利用小鼠遗传学来检验我们的假设，即FoxJ1在牙齿发育过程中成釉细胞和成牙本质细胞的细胞分化中发挥作用。我们将验证我们的假设，即PITX2在牙齿发育过程中与其他转录因子一起调节FoxJ1的表达。此外，FoxJ1与PITX2在物理上相互作用，并以正反馈的方式自动调节其启动子。我们将验证我们的假设，即FoxJ1与PITX2和其他牙齿特异转录因子相互作用，调节牙齿发育的钟声晚期和分泌前阶段。识别与颅面/牙齿发育有关的新基因将增加我们对正常胚胎发育所需的基本发育程序的了解。了解这些成分如何相互作用促进正常的头面部发育将进一步加深我们对遗传缺陷的理解。然后我们就可以推广抑制严重颅面畸形的方法。 公共卫生相关性：识别与颅面/牙齿发育有关的新基因将增加我们对正常胚胎发育所需的基本发育程序的了解。了解这些成分如何相互作用促进正常的头面部发育将进一步加深我们对遗传缺陷的理解。然后，一旦将分子基础分配给特定的缺陷或组件，我们就可以推广抑制严重颅面异常的方法。

DESCRIPTION (provided by applicant): In recent years a number of new genes have been identified that are involved in tooth morphogenesis. Though much progress has been made in identifying new genes and the signaling mechanisms that regulate morphogenetic stages of tooth development have been documented, the transcriptional mechanisms that regulate cytodifferentiation of the odontoblasts and ameloblasts are poorly understood. Better understanding of the mechanistic aspect of this process is necessary, not only to understand normal tooth morphogenesis, but also to regenerate teeth, and eventually be able to develop and deliver better therapeutic strategies. Our lab has identified FoxJ1 as a new transcription factor involved in late stage tooth and craniofacial morphogenesis. FoxJ1 (also known as HFH-4, FHKL-13) belongs to the fork-head family of genes, containing a fork-head (also known as winged helix) DNA binding domain is known to regulate development via cell fate determination. Our preliminary data reveals FoxJ1 expression in the mouse molar inner dental epithelium from E18.5 onwards and in the pre-ameloblasts and odontoblasts during neonate day 1. It is also expressed in the oral epithelium and sub-mandibular salivary gland during E17.5 and neonate day 1. Our transient transfection data indicates that FoxJ1 is activated by, and also physically interacts with PITX2, a homeobox transcription factor gene involved in early craniofacial/tooth development. The overall goal of this proposal is to test our hypothesis that FoxJ1 plays a role in cytodifferentiation of ameloblasts and odontoblasts during tooth development using mouse genetics. We will test our hypothesis that PITX2 regulates FoxJ1 expression in concert with other transcription factors during tooth development. Moreover, FoxJ1 physically interacts with PITX2 and auto-regulates its promoter in a positive feedback fashion. We will test our hypothesis that FoxJ1 interacts with PITX2 and other tooth specific transcription factors to regulate late bell and pre-secretory stages of tooth development. The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies. PUBLIC HEALTH RELEVANCE: The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies once a molecular basis has been assigned to a specific defect or component.