Development of Cranial Motor Neurons

这项拟议研究的长期目标是了解调节神经元的机制。 哺乳动物的迁徙。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，在那里它们组装成复杂的网络，负责复杂的功能，如 学习和行为。许多人类神经疾病是由于神经元的异常迁移或 迁移失败。因此，有必要了解介导特定物种迁移的机制。 神经元类型，因此人类大脑疾病的原因和潜在的治疗方法最终可以 已确认身份。 拟议的工作利用了斑马鱼和斑马鱼面部分支运动神经元(FBMN)的迁移 小鼠后脑作为哺乳动物神经元迁移的模型。以前的工作表明，一个 跨膜蛋白斜视(Stbm)是FBMN在斑马鱼体内迁移所必需的。STBM一直是 它作为无翼/Wnt信号通路的一个组成部分在介导极化细胞中的作用得到了很好的研究 苍蝇和脊椎动物上皮细胞层的行为和图案化事件(平面细胞极性/PCP)。 然而，我们积累了令人信服的初步证据，表明在FBMN迁移期间，Stbm可能 其功能独立于Wnt/PCP信号通路的其他组件。因此，看起来 Stbm和Pricklel(Pk1)是一种可能与Stbm结合的细胞质蛋白，使用新的分子和细胞 调节FBMN迁移的机制。在目标1中，STBM内不同领域的作用，以及两个领域的作用 在斑马鱼的FBMN迁移中，可能与STBM相互作用的蛋白质将用增益和损失函数来研究 接近了。在目标2中，需要Stbm和Pk1功能的细胞(S)的恒等式 FBMN的迁移将使用功能丧失和细胞移植的方法来确定。在目标3中， STBM和其他PCP组分在小鼠FBMN迁移中的作用将通过详细的 突变小鼠的表达研究和分析。总之，这些实验将产生新的洞察力 脊椎动物后脑中的神经元迁移机制。

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 intricate networks responsible for complex functions such as learning 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. 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. It therefore appears that Stbm and Pricklel (Pk1), a cytoplasmic protein that potentially binds Stbm, use novel molecular and cellular mechanisms to regulate FBMN migration. In Aim 1, the roles of various domains within Stbm, and of two putative Stbm-interacting proteins, in FBMN migration in zebrafish will be studied using gain- and loss-offunction approaches. In Aim 2, the identity of the cell(s) in which Stbm and Pk1 functions are needed for FBMN migration will be determined using loss-of-function and cell transplantation methods. In Aim 3, the roles of Stbm and other PCP components in FBMN migration in mouse will be evaluated through detailed expression studies and analyses of mutant mice. Together, these experiments will generate novel insight into neuronal migration mechanisms in the vertebrate hindbrain.