Mechanisms of FoxJ1 Tooth Morphogenesis

描述（由申请人提供）：近年来，已经鉴定了许多参与牙齿形态发生的新基因。虽然在识别新基因方面取得了很大进展，并且已经记录了调节牙齿发育的形态发生阶段的信号传导机制，但是调节成牙本质细胞和成釉细胞的细胞分化的转录机制知之甚少。更好地了解这一过程的机制方面是必要的，不仅要了解正常的牙齿形态发生，而且要再生牙齿，并最终能够开发和提供更好的治疗策略。我们的实验室已经确定FoxJ 1作为一个新的转录因子参与晚期牙齿和颅面形态发生。FoxJ 1（也称为HFH-4，FHKL-13）属于叉头基因家族，含有一个叉头（也称为翼螺旋）DNA结合结构域，已知通过细胞命运决定来调节发育。我们的初步数据显示，FoxJ 1表达在小鼠磨牙内牙上皮从E18.5起，并在前成釉细胞和成牙本质细胞在新生儿第1天。它也在E17.5和新生儿第1天的口腔上皮和下颌下唾液腺中表达。我们的瞬时转染数据表明，FoxJ 1被激活，并与PITX 2，一个同源框转录因子基因参与早期颅面/牙齿发育的物理相互作用。这项建议的总体目标是测试我们的假设，即FoxJ 1在成釉细胞和成牙本质细胞的细胞分化中发挥作用，在牙齿发育过程中使用小鼠遗传学。我们将测试我们的假设，即PITX 2调节FoxJ 1的表达与其他转录因子在牙齿发育过程中。此外，FoxJ 1与PITX 2发生物理相互作用，并以正反馈方式自动调节其启动子。我们将测试我们的假设，FoxJ 1与PITX 2和其他牙齿特异性转录因子相互作用，以调节晚钟和牙齿发育的前分泌阶段。颅面/牙齿发育中涉及的新基因的鉴定将增加我们对正常胚胎发生所需的基本发育程序的知识。了解这些组成部分如何相互作用，以促进正常颅面发育将进一步我们对遗传缺陷的理解。然后，我们可以推广抑制严重颅面畸形的方法。 公共卫生相关性：颅面/牙齿发育中涉及的新基因的鉴定将增加我们对正常胚胎发生所需的基本发育程序的知识。了解这些组成部分如何相互作用，以促进正常颅面发育将进一步我们对遗传缺陷的理解。然后，我们可以促进方法，以抑制严重的颅面异常，一旦分子基础已被分配到一个特定的缺陷或组件。

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.