Regulation of neuronal migration by second messagers

描述(申请人提供)：未成熟神经元的引导迁移 从他们的出生地到最终目的地构成了 有序的细胞结构、特定的突触连接和复杂的功能 神经系统的一部分。尽管在以下方面取得了相当大的进展 确定主要的迁移途径以及涉及的基因和分子 在迁移中，定向细胞运动背后的细胞机制 仍然难以捉摸。我们假设神经元的迁移可以通过 第二信使，以及这些信使的不同时空模式 细胞内信号可以对速度和方向产生明显的影响 关于迁徙。为了验证这一假设，我们开发了一种无胶质细胞的培养方法。 单个小脑颗粒神经元定向迁移的系统 在玻璃盖板上实时观察。这一创新的文化体系 允许高分辨率定量成像和细胞内操作 单个迁移神经元不同细胞区域的第二信使， 从而使我们能够直接检查第二信使在 调节神经元的迁移。在这项研究中，我们将特别确定 细胞内钙离子及其时空模式是如何调节这一速率的 以及颗粒细胞迁移的方向 高分辨率Ca~(2+)成像和空间受限光激活释放 笼子里的钙离子。同样，我们还将确定cAMP在调节 定向的细胞运动。一个常见的方案是细胞内信号，而不是 不仅内在地调节定向的细胞运动，而且还调节动作 关于神经元迁移的细胞外线索。我们的长期目标是澄清 控制和调节幼虫迁徙的细胞机制 神经元。这些独特和创新的研究可以产生大量的数据 可以建立哪些重要的未来研究来获得重要的见解 关于神经元迁移的分子和细胞机制， 这对于我们理解大脑发育以及 不当行为所致脑部疾病潜在治疗方法的研究进展 神经元迁移

DESCRIPTION (provided by applicant): Guided migration of the immature neurons from their birthplace to the final destination constitutes the basis for ordered cytoarchitecture, specific synaptic connectivity, and complex function of the nervous system. Although considerable progress has been made in identifying the major migratory pathways and the genes and molecules involved in migration, the cellular mechanisms underlying the directed cell movement remain elusive. We hypothesize that neuronal migration can be regulated by second messengers, and different spatial and temporal patterns of these intracellular signals can exert distinct influences on the rate and direction of migration. To test this hypothesis, we have developed a glial-free culture system in which directional migration of single cerebellar granule neurons can be observed on glass coverslip in real time. This innovative culture system allows high-resolution quantitative imaging and intracellular manipulation of second messengers in different cellular regions of a single migrating neuron, thus enabling us to directly examine the role of second messengers in regulating neuronal migration. In this study, we will specifically determine how intracellular Ca2+ and its spatial and temporal patterns regulate the rate as well as the direction of granule cell migration using a combination of high-resolution Ca2+ imaging and spatially-restricted photoactivated release of caged Ca2+. Similarly, we will also determine the role of cAMP in regulating directed cell movement. A common scheme is the intracellular signals that not only intrinsically regulate directed cell movement but also mediate the actions of extracellular cues on neuronal migration. Our long-term goal is to elucidate the cellular mechanisms that control and regulate the migration of young neurons. These unique and innovative studies can generate a body of data upon which significant future research can be built to gain important insights towards the molecular and cellular mechanisms underlying neuronal migration, which is essential to our understanding of brain development as well as the development of potential treatments for brain disorders resulted from improper neuronal migration