Development of Cranial Motor Neurons

描述(申请人提供)：这项拟议研究的长期目标是了解哺乳动物神经元迁移的中介机制。在脊椎动物胚胎中，神经元经常长距离迁移到它们的最终位置，在那里它们组装成控制生理和行为的复杂网络。当神经元异常迁移或迁移失败时，人类的许多神经疾病就会发生。因此，了解调节特定类型神经元迁移的机制是至关重要的，这样才能最终确定人类大脑疾病的原因和潜在的治疗方法。我们的研究还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而受损的大脑区域的努力。这项拟议的工作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。以往的研究表明，斑马鱼FBMN的迁移需要一种跨膜蛋白--斜视蛋白(Stbm)。STBM作为无翼/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)中介导极化的细胞行为和图案化事件，因此得到了很好的研究。然而，我们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Prickle1a(Pk1a)，一种可能与Stbm结合的细胞质蛋白，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，将使用功能获得和功能丧失的方法研究斑马鱼FBMN迁移过程中STBM内不同结构域以及与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的方法来确定FbmN迁移所必需的Stbm和Pk1a功能所在的细胞类型(S)的身份。最后，将通过对突变小鼠的详细表型分析来评估STBM和其他PCP成分在FBMN在小鼠体内迁移中的作用。 公共卫生相关性：拟议的神经元迁移研究具有双重意义。1)许多人类神经系统疾病是由神经元迁移缺陷引起的。因此，必须了解这些疾病的潜在机制，以便能够确定这些疾病的原因和可能的补救措施。2)干细胞研究中的一个持续挑战是了解如何诱导干细胞来源的神经元准确地迁移到因损伤或疾病而受损的脑区。因此，我们的研究可以影响提高干细胞疗法治疗神经元损伤和疾病的有效性的努力。

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.