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The Role of Primary Cilia in Murine Craniofacial Development

初级纤毛在小鼠颅面发育中的作用

基本信息

批准号：
8612175
负责人：
Samantha A Brugmann
金额：
$ 39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-13 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8612175
关键词：
Address Affect Apoptosis Back Carrier Proteins Cells Cephalic Cilia Data Defect Development Disease Dissociation Dorsal Ectoderm Embryo Environment Erinaceidae Etiology Face Frontonasal Prominence Genetic Growth Growth and Development function Jaw Maintenance Mandible Mandibular Prominence Mediating Membrane Mesoderm Microtubules Modeling Molecular Movement Mus Mutation Myoblasts Neural Crest Cell Neuroectoderm Neuroglia Organelles Pattern Phenotype Play Process Production Prosencephalon Protein Isoforms Proteins Reading Role Signal Transduction Sonic Hedgehog Pathway Testing Tissues Tongue Work base body system ciliopathy craniofacial craniofacial complex insight migration mutant neuronal cell body novel prevent progenitor protein complex public health relevance research study restoration smoothened signaling pathway transcription factor

项目摘要

Project Summary Primary cilia are ubiquitous organelles that receive and transduce molecular signals from the cell's molecular environment. Kif3a is an intraflagellar transport protein necessary for the extension and function of primary cilia. Conditional loss of Kif3a in cranial neural crest cells results in severe midfacial expansion and the loss of a tongue (aglossia). These phenotypes, along with our preliminary data, suggest that loss of Kif3a causes aberrant Sonic hedgehog (Shh) activity. Our objective is to determine how loss of Kif3a in neural crest cells affects Shh signaling within the craniofacial complex. In our first aim we will test the hypothesis that loss of Kif3a prevents the formation of the Gli3 repressor in neural crest cells of the developing midface. We will examine the role Kif3a plays in Gli3 processing and test if reintroduction of Gli3 repressor can rescue the midfacial phenotype. In our second aim we test if loss of Kif3a in neural crest cells disrupts Shh dependent signaling centers in neuroectoderm and facial ectoderm that are necessary for development and growth of the midface. This aim tests the hypothesis that the midfacial phenotype in Kif3a mutants is caused by a secondary, non-cell autonomous mechanism. In our third aim we test the hypothesis that loss of Kif3a prevents formation of Gli activator in the developing tongue and lower jaw. Loss of the activator subsequently leads to a loss-of-Shh function. We will compare the molecular mechanism of aglossia between Kif3a conditional knock-outs and another, Shh-dependent aglossia model. Finally, we will determine the fate of mesodermally derived muscle precursor cells of the tongue in Kif3a mutants. Taken together, these studies will lend essential insight into the mechanism of primary cilia function in processing a Shh signal within the developing craniofacial complex. We expect our studies will provide novel insight into the etiology of craniofacial ciliopathies.

项目概要初级纤毛是普遍存在的细胞器，它接收和转导来自纤毛的分子信号。细胞的分子环境。 Kif3a 是一种鞭毛内转运蛋白，是初级纤毛的延伸和功能。颅神经嵴细胞中 Kif3a 的条件性缺失导致严重的中面部扩张和舌头丧失（失语症）。这些表型，结合我们的初步数据，表明 Kif3a 的丢失会导致异常的 Sonic 刺猬（嘘）活动。我们的目标是确定神经嵴细胞中 Kif3a 的缺失如何影响 Shh 颅面复合体内的信号传导。在我们的第一个目标中，我们将测试以下假设： Kif3a 阻止发育中神经嵴细胞中 Gli3 阻遏蛋白的形成中脸。我们将研究 Kif3a 在 Gli3 处理中所扮演的角色，并测试是否重新引入 Gli3 阻遏物可以挽救中面部表型。在我们的第二个目标中，我们测试 Kif3a 是否丢失神经嵴细胞破坏神经外胚层和面部的Shh依赖性信号中心中面部发育和生长所必需的外胚层。这个目标测试了假设 Kif3a 突变体的中面部表型是由次生非细胞引起的自主机制。在我们的第三个目标中，我们测试了以下假设：Kif3a 的丢失会阻止发育中的舌头和下颌中 Gli 激活剂的形成。活化剂丢失随后导致“嘘”功能的丧失。我们将比较分子机制 Kif3a 条件性敲除和另一种依赖于 Shh 的失语模型之间的失语。最后，我们将确定舌头中胚层来源的肌肉前体细胞的命运在 Kif3a 突变体中。总而言之，这些研究将为我们深入了解这一机制提供重要的见解。初级纤毛的功能是在发育中的颅面复合体中处理“Shh”信号。我们期望我们的研究将为颅面纤毛病的病因学提供新的见解。