Role of Wnt/Planar Cell Polarity Proteins in Motor Neuron Migration

描述(申请人提供)：神经元迁移是中枢神经系统中功能神经网络形成所必需的发育过程。神经元迁移缺陷是人类疾病的根本原因，如无脑畸形和脑室周围异位。为了更好地了解神经元迁移的控制机制，我们的实验室研究了小鼠脑干中面部分支运动神经元(FBMN)的迁移。这些神经元控制着颌骨和面部的运动，在发育过程中经历了典型的尾部迁移。Wnt/Planar Cell Polality(PCP)通路中的几个分子已被证明调节FBMN在斑马鱼和小鼠中的迁移，但大多数分子的功能是决定尾部迁移的程度。另一方面，我们发现非典型的钙粘蛋白Celsr1调节迁移的方向性，因为在Celsr1突变体中，FBMN的子集向错误的方向迁移。在后脑，Celsr1以动态方式在几个组织中表达，包括底板和脑室带，但不在FBMN细胞体中表达。为了了解Celsr1如何调节方向性，我们将使用Celsr1条件等位基因和组织特异性Cre重组酶系，检查删除Celsr1功能在不同后脑部分或底板细胞中的影响。使用各种标记，我们将测试各种假设，这些假设可以解释这些条件突变中潜在的FBMN迁移缺陷。阐明Celsr1调节FBMN迁移方向性的细胞机制可能有助于理解神经元迁移障碍和其他类型的细胞运动，如转移，因为Wnt/PCP基因在许多癌症中被解除调控。 与公共健康相关：这项拟议的研究旨在确定某些分子如何控制大脑中涉及神经元运动的重要发育过程。神经元在胚胎发育期间不能正确移动可能会导致人类严重的神经疾病。在创建和建立治疗这些疾病的方法之前，必须更好地了解这些分子控制神经元运动的机制。

DESCRIPTION (provided by applicant): Neuronal migration is a developmental process essential to the formation of functional neural networks in the central nervous system. Defective neuronal migration is an underlying cause of human diseases such as lissencephaly and periventricular heterotopia. To better understand the mechanisms controlling neuronal migration, our laboratory studies the migration of facial branchimotor neurons (FBMNs) in the mouse brain stem. These neurons, which control jaw and facial movements, undergo a characteristic caudal migration during development. Several molecules of the Wnt/Planar Cell Polarity (PCP) pathway have been demonstrated to regulate FBMN migration in zebrafish and mouse, but most function to determine the extent of caudal migration. We have discovered that the atypical cadherin Celsr1, on the other hand, regulates the directionality of migration, since a subset of FBMNs migrates in the wrong direction in Celsr1 mutants. In the hindbrain, Celsr1 is expressed in a dynamic fashion in several tissues including the floor plate and ventricular zone, but not in FBMN cell bodies. To understand how Celsr1 regulates directionality, we will examine the effect of deleting Celsr1 function in different hindbrain segments or floor plate cells, using a Celsr1 conditional allele and tissue-specific Cre recombinase lines. Using a variety of markers, we will test various hypotheses that could explain potential FBMN migration defects in these conditional mutants. Elucidating the cellular mechanisms through which Celsr1 regulates the directionality of FBMN migration could have implications for understanding neuronal migration disorders and other types of cell movement such as metastasis, since Wnt/PCP genes are deregulated in many cancers. PUBLIC HEALTH RELEVANCE: The proposed research aims to identify how certain molecules control an important developmental process in the brain involving the movement of neurons. The failure of neurons to move properly during embryonic development can result in severe neurological diseases in humans. Before therapies for those diseases can be created and established, the mechanisms by which these molecules control neuronal movement must be better understood.