Role of Cilia in Mammalian Tooth Patterning

描述(申请人提供)：纤毛是以微管为基础的细胞器，长期以来在大多数哺乳动物细胞上观察到。虽然它们的存在已为人所知，但它们在哺乳动物发育和信号传递中的不同功能却知之甚少。纤毛最近被证明在Hedgehog信号、PDGFRAA信号和调节Wnt反应中是必不可少的。小鼠的牙齿发育是在胚胎发育期间开始的，需要口腔外胚层和底层间充质之间复杂的信号传递。随着发育的进行，外胚层细胞对包括釉质在内的牙齿表面结构的贡献，而间充质分化为许多类型的细胞，包括牙髓细胞和成牙本质细胞，它们在釉质下面分泌牙本质。在成牙本质细胞上发现了纤毛，纤毛功能部分丧失的小鼠在牙齿的图案方面存在缺陷，这表明纤毛在小鼠牙列的图案形成和发育过程中发挥了作用。这项应用的目的是利用纤毛基因Tg737的条件等位基因和可诱导的Cre重组酶在牙齿发育的两个不同阶段扰乱纤毛，研究纤毛在牙齿形成中的作用。纤毛在牙齿起始和形态发生中的作用将通过检测牙齿的模式和发育来研究。纤毛断裂后，将使用组织学和原位杂交对生成的牙齿进行检查。总体而言，所获得的数据将为更详细的研究提供初步支持。 与公共卫生相关：越来越多的多发性综合征与纤毛和/或基底体的蛋白质突变有关，患者的牙齿数量或结构明显缺陷。为了更好地了解纤毛/基底体缺陷是如何导致牙列变化的，额外的工作是必要的。

DESCRIPTION (provided by applicant): Cilia are microtubule-based organelles that have long been observed on most mammalian cells. While their presence has been known, their diverse functions in mammalian development and signaling are poorly understood. Cilia have recently been shown to be essential for hedgehog signaling, PDGFRAA signaling and in modulating Wnt responses. Tooth development in mice is initiated during embryogenesis and requires complex signaling between the oral ectoderm and underlying mesenchyme. As development progresses, ectodermal cells contribute to the superficial structures of the tooth including the enamel while the mesenchyme differentiates into many cell types including the dental pulp cells and odontoblasts which secrete dentin below the enamel. Cilia have been identified on the odontoblasts and mice with partial loss of cilia function have defects in the patterning of the teeth suggesting a role for cilia during the patterning and development of the murine dentition. The goal of this application is to investigate cilia function in tooth formation using a conditional allele of the cilia gene Tg737 and an inducible Cre recombinase to disrupt cilia at two distinct stages of tooth development. The role of cilia during tooth initiation and morphogenesis will be investigated by examining the patterning and development of teeth. After cilia disruption, the resulting teeth will be examined using histology and in situ hybridization. Overall the data obtained will provide preliminary to support more detailed studies. PUBLIC HEALTH RELEVANCE: A growing number of pleiotropic syndromes have been associated with mutations in proteins localized to the cilium and/or basal body and defects in tooth number or structure are evident in patients. In order to better understand how cilia/basal body defects lead to alterations in the dentition, additional work is necessary.