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

神经元迁移是中枢神经系统功能神经网络形成的重要发育过程。有缺陷的神经元迁移是无脑畸形和心室周围异位等人类疾病的潜在原因。为了更好地了解神经元迁移的控制机制，本实验室研究了小鼠脑干中面部分支运动神经元（FBMNs）的迁移。这些控制下颌和面部运动的神经元在发育过程中经历了典型的尾侧迁移。Wnt/Planar Cell Polarity （PCP）通路的几个分子已被证明可以调节斑马鱼和小鼠的FBMN迁移，但大多数的功能是决定尾侧迁移的程度。我们发现，另一方面，非典型钙粘蛋白Celsr1调节迁移的方向性，因为在Celsr1突变体中，fbmn的一个子集向错误的方向迁移。在后脑中，Celsr1在包括底板和心室区在内的几个组织中以动态方式表达，但在FBMN细胞体中不表达。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，研究在不同的后脑片段或底板细胞中删除Celsr1功能的影响。使用各种标记，我们将测试各种假设，可以解释这些条件突变体中潜在的FBMN迁移缺陷。阐明Celsr1调控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基因在许多癌症中是不受调控的。

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.