Mechanisms of Tangential Neuron Migration

切向神经元迁移的机制

基本信息

批准号：
9094708
负责人：
Cecilia B Moens
金额：
$ 40.32万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
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：
2013-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094708
关键词：
Actins Affect Anterior Apical Axon Behavior Biological Models Birth Place Brain Cell Adhesion Cell Communication Cell Culture Techniques Cell Shape Cell division Cell physiology Cells Cellular biology Cerebellum Characteristics Cloning Cytoplasmic Granules Development Disease Dominant-Negative Mutation Environment Epithelial Cells Epithelium Extracellular Matrix Degradation Face Facial nerve structure Fiber Gene Transfer Techniques Genes Genetic Genetic Screening Goals Health Human Image Imaging Device Immigration Life Link Location Malignant Neoplasms Membrane Protein Traffic Mitotic Modeling Molecular Neural Crest Cell Neural Tube Closure Neurodevelopmental Disorder Neurons Pathway interactions Process Proteins Radial Role Signal Transduction Spinal Dysraphism Stereotyping Stream Surface System Testing Tissues Transgenic Organisms Ventricular Visual Wing Zebrafish analytical tool cell behavior cell motility cell type ciliopathy cilium biogenesis directional cell fly forward genetics gastrulation hindbrain in vivo migration mutant nerve stem cell neuroepithelium planar cell polarity polarized cell reconstitution research study reverse genetics tool

项目摘要

DESCRIPTION (provided by applicant): Almost all neurons in the vertebrate brain are "foreign born" - that is, they are born at or near the ventricular surface and then migrate to another location where they make their connections and carry out their specialized functions. Neuronal migrations can be radial, parallel to the api- co-basal axis of the neuroepithelium, or they can be tangential: orthogonal to the apical-basal axis - i.e., in the plane of the neuroepithelium. With te goal of discovering genetic mechanisms regulating directed neuronal migration, we have established the facial branchiomotor neurons (FBMNs; cranial nerve VII), which undergo a stereotyped and evolutionarily conserved tangen- tial migration from hindbrain rhombomere (r)4 to r6, as a model system in our lab. Forward ge- netic screens in our lab and others have identified multiple core components of the Planar Cell Polarity (PCP) pathway as being essential for FBMN migration. The PCP pathway is best under- stood as a cell contact-dependent molecular mechanism for generating and transmitting polarity between cells in the plane of an epithelium. However PCP has been implicated in a growing number of cell migrations during development and disease states. Currently no coherent model exists for how PCP regulates directional cell migration. This is mainly because the polarized cell- cell interactions that defin PCP are difficult to reconstitute in cell culture; we must therefore attack the problem in vivo. Th zebrafish model, with its exquisite live imaging, facile transgen- esis and powerful forward and reverse genetics tools, affords us this opportunity. We hypothe- size that direct PCP signaling between the planar-polarized cells of the neuroepithelium and the motile FBMNs polarizes FBMN protrusive activity in the direction of migration. We pro- pose to test the predictions of thi model first by identifying the cells in the migratory environ- ment that are responsible for directing migration (Aim 1), and then by elucidating how PCP sig- naling within the FBMNs affects their behavior in vivo (Aim 2). Furthermore in Aim 2 we will discover how interactions between migrating FBMNs and the surrounding neuroepithelium in- fluence PCP protein localization and protrusive activity in the FBMNs. Finally, we propose to enrich our understanding of PCP-dependent neuron migration through the cloning of FBMN migration mutants we have identified in a forward genetic screen (Aim 3).

描述（由申请人提供）：脊椎动物大脑中的几乎所有神经元都是“外来的”——也就是说，它们出生在脑室表面或附近，然后迁移到另一个位置，在那里它们建立连接并执行其专门功能。神经元迁移可以是径向的，平行于神经上皮的顶端基底轴，或者它们可以是切向：与顶底轴正交 - 即在神经上皮平面中。为了发现调节定向神经元迁移的遗传机制，我们建立了面部鳃运动神经元（FBMN；颅神经 VII），它经历从后脑菱形核 (r)4 到 r6 的定型且进化上保守的切向迁移，作为我们实验室的模型系统。我们实验室和其他实验室的正向遗传筛选已确定平面细胞极性 (PCP) 途径的多个核心成分对于 FBMN 迁移至关重要。 PCP 途径最好理解为一种细胞接触依赖性分子机制，用于在上皮平面的细胞之间产生和传递极性。然而，PCP 与发育和疾病状态期间越来越多的细胞迁移有关。目前还没有关于 PCP 如何调节定向细胞迁移的一致模型。这主要是因为定义 PCP 的极化细胞间相互作用很难在细胞培养物中重建；因此，我们必须解决体内的问题。斑马鱼模型以其精美的实时成像、简便的转基因以及强大的正向和反向遗传学工具为我们提供了这个机会。我们假设神经上皮平面极化细胞和运动 FBMN 之间的直接 PCP 信号传导使 FBMN 的突出活动沿迁移方向极化。我们建议首先通过识别迁移环境中负责指导迁移的细胞（目标 1）来测试该模型的预测，然后阐明 FBMN 内的 PCP 信号传导如何影响其体内行为（目标 2）。此外，在目标 2 中，我们将发现迁移的 FBMN 与周围神经上皮之间的相互作用如何影响 PCP 蛋白定位和 FBMN 中的突出活性。最后，我们建议通过克隆我们在正向遗传筛选中发现的 FBMN 迁移突变体来丰富我们对 PCP 依赖性神经元迁移的理解（目标 3）。