Development of Cranial Motor Neurons

描述（由申请人提供）：拟议研究的长期目标是了解介导哺乳动物神经元迁移的机制。在脊椎动物胚胎中，神经元经常长途迁移到它们的最终位置，在那里它们聚集成控制生理和行为的复杂网络。许多人类神经系统疾病是由于神经元迁移异常或迁移失败造成的。因此，了解介导特定神经元类型迁移的机制至关重要，这样才能最终确定人类大脑疾病的原因和潜在的补救措施。我们的研究也可能影响诱导干细胞来源的神经元准确迁移到因损伤或疾病受损的大脑区域的努力。本研究采用斑马鱼和小鼠后脑中面部分支运动神经元（fbmn）的迁移作为哺乳动物神经元迁移的模型。先前的研究表明，跨膜蛋白斜视（Stbm）是斑马鱼FBMN迁移所必需的。Stbm作为无翅/Wnt信号通路的一个组成部分，在果蝇和脊椎动物的上皮细胞层（平面细胞极性/PCP）中介导极化细胞行为和模式事件，已经得到了很好的研究。然而，我们已经积累了令人信服的初步证据，表明在FBMN迁移过程中，Stbm可能独立于Wnt/PCP信号通路的其他组成部分发挥作用。因此，我们假设Stbm和可能结合Stbm的细胞质蛋白Prickle1a （Pk1a）使用新的分子和细胞机制来调节FBMN的迁移。我们提出了几种方法来揭示这些机制。首先，在斑马鱼FBMN迁移过程中，将使用功能增益和功能损失的方法研究Stbm内的各种结构域以及与Stbm相互作用的三个基因的作用。接下来，将使用功能丧失和细胞移植方法确定Stbm和Pk1a功能对FBMN迁移所必需的细胞类型。最后，通过对突变小鼠的详细表型分析，评估Stbm和其他PCP成分在小鼠FBMN迁移中的作用。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand the mechanisms that mediate neuronal migration in mammals. In the vertebrate embryo, neurons frequently migrate long distances to reach their final positions, where they assemble into complex networks that control physiology and behavior. Many human neurological disorders result when neurons either migrate aberrantly or fail to migrate. Therefore, it is essential to understand the mechanisms mediating migration of specific neuronal types, so that the causes of and potential remedies for human brain disorders can eventually be identified. Our studies may also impact efforts to induce stem cell-derived neurons to migrate accurately into brain regions damaged by injury or disease. The proposed work employs the migration of facial branchiomotor neurons (FBMNs) in the zebrafish and mouse hindbrain as a model for neuronal migrations in mammals. Previous work demonstrated that a transmembrane protein Strabismus (Stbm) was necessary for FBMN migration in zebrafish. Stbm has been well studied for its role as a component of the wingless/Wnt signaling pathway in mediating polarized cellular behaviors and patterning events in an epithelial cell layer (planar cell polarity/PCP) in flies and vertebrates. However, we have accumulated compelling preliminary evidence that, during FBMN migration, Stbm may function independently of other components of the Wnt/PCP signaling pathway. We therefore hypothesize that Stbm and Prickle1a (Pk1a), a cytoplasmic protein that potentially binds Stbm, use novel molecular and cellular mechanisms to regulate FBMN migration. We propose several approaches to uncover these mechanisms. First, the roles of various domains within Stbm, and of three genes that interact with stbm, during FBMN migration in zebrafish will be studied using gain- and loss-of-function approaches. Next, the identity of the cell type(s) in which Stbm and Pk1a functions are necessary for FBMN migration will be determined using loss-of-function and cell transplantation methods. Finally, the roles of Stbm and other PCP components in FBMN migration in mouse will be evaluated through detailed phenotypic analyses of mutant mice. PUBLIC HEALTH RELEVANCE: The proposed studies of neuronal migration have two-fold significance. 1) Many human neurological disorders result from defective neuronal migration. Therefore, it is essential to understand the underlying mechanisms so that the causes of and potential remedies for these diseases can be identified. 2) An ongoing challenge in stem cell research is to understand how stem cell-derived neurons can be induced to migrate accurately into brain regions damaged by injury or disease. Our studies can therefore impact efforts to increase the efficacy of stem cell therapies to treat neuronal injury and disease.