Role of Cilia in Mammalian Tooth Patterning

描述（由申请人提供）：纤毛是基于微管的细胞器，长期以来在大多数哺乳动物细胞中观察到。虽然它们的存在是已知的，但它们在哺乳动物发育和信号传导中的多种功能却知之甚少。纤毛最近被证明是必不可少的刺猬信号，PDGFRA信号和调节Wnt反应。小鼠的牙齿发育在胚胎发生期间开始，并且需要口腔外胚层和下面的间充质之间的复杂信号传导。随着发育的进展，外胚层细胞有助于牙齿的表面结构，包括釉质，而间充质分化成许多细胞类型，包括牙髓细胞和成牙本质细胞，其在釉质下分泌牙本质。纤毛已经在成牙本质细胞上被鉴定，纤毛功能部分丧失的小鼠在牙齿的图案形成中具有缺陷，这表明纤毛在小鼠牙列的图案形成和发育期间的作用。本申请的目的是使用纤毛基因Tg737的条件等位基因和诱导型Cre重组酶在牙齿发育的两个不同阶段破坏纤毛来研究纤毛在牙齿形成中的功能。通过研究牙齿的图案和发育，将研究纤毛在牙齿发生和形态发生中的作用。纤毛破坏后，将使用组织学和原位杂交检查所得牙齿。总体而言，所获得的数据将为支持更详细的研究提供初步资料。 公共卫生相关性：越来越多的多效性综合征与纤毛和/或基体蛋白质的突变有关，患者的牙齿数量或结构缺陷明显。为了更好地了解纤毛/基体缺陷如何导致牙列改变，需要进行额外的工作。

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.