Mechanisms of FoxJ1 Tooth Morphogenesis

描述（由申请人提供）：近年来发现了一些与牙齿形态发生有关的新基因。虽然在鉴定新基因和调节牙齿发育形态发生阶段的信号机制方面已经取得了很大进展，但调节成牙细胞和成釉细胞分化的转录机制尚不清楚。更好地了解这一过程的机制方面是必要的，不仅要了解正常牙齿的形态发生，而且要使牙齿再生，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FoxJ1是一个新的转录因子参与晚期牙齿和颅面形态发生。FoxJ1（也被称为hhh -4， FHKL-13）属于叉头基因家族，包含一个叉头（也被称为翼螺旋）DNA结合域，已知通过决定细胞命运来调节发育。我们的初步数据显示FoxJ1在E18.5以后的小鼠磨牙内上皮以及在新生儿第1天的前成釉细胞和成牙细胞中表达。在E17.5和新生儿第1天，它也在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FoxJ1被PITX2激活，并与PITX2相互作用，PITX2是一种参与早期颅面/牙齿发育的同源盒转录因子基因。本研究的总体目标是利用小鼠遗传学来验证我们的假设，即FoxJ1在牙齿发育过程中成釉细胞和成牙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，FoxJ1与PITX2和其他牙齿特异性转录因子相互作用，调节牙齿发育的钟晚期和分泌前阶段。颅面/牙齿发育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认识。了解这些成分如何相互作用以促进正常颅面发育将进一步加深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。

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.