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

神经元迁移是中枢神经系统中功能性神经网络形成所必需的发育过程。缺陷的神经元迁移是人类疾病如无脑畸形和脑室周围异位症的潜在原因。为了更好地了解控制神经元迁移的机制，我们的实验室研究了小鼠脑干中面鳃运动神经元（FBMNs）的迁移。这些神经元，控制下巴和面部运动，在发育过程中经历了一个特征性的尾部迁移。Wnt/平面细胞极性（PCP）途径的几种分子已被证明可以调节斑马鱼和小鼠的FBMN迁移，但大多数功能是决定尾部迁移的程度。另一方面，我们发现非典型钙粘蛋白Celsr 1调节迁移的方向性，因为在Celsr 1突变体中，FBMNs的一个子集以错误的方向迁移。在后脑中，Celsr 1在包括底板和脑室区在内的几种组织中以动态方式表达，但不在FBMN细胞体中表达。为了了解Celsr 1如何调节方向性，我们将使用Celsr 1条件等位基因和组织特异性Cre重组酶系，研究在不同的后脑节段或底板细胞中删除Celsr 1功能的影响。使用各种标记，我们将测试各种假设，可以解释潜在的FBMN迁移缺陷，在这些条件突变体。阐明Celsr 1调节FBMN迁移方向性的细胞机制可能对理解神经元迁移障碍和其他类型的细胞运动（如转移）具有意义，因为Wnt/PCP基因在许多癌症中被解除调节。

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.