Regulation of neuronal migration by second messagers

描述（由申请人提供）：未成熟神经元的引导迁移 从他们的出生地到最终目的地， 有序的细胞结构、特异性突触连接和复杂功能 的神经系统。虽然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相关的基因和分子 在迁移中，细胞定向运动的细胞机制 仍然难以捉摸我们假设神经元迁移可以通过 第二信使，以及它们的不同空间和时间模式 细胞内信号可以对细胞凋亡的速率和方向产生不同的影响， 移民。为了验证这一假设，我们开发了一种无胶质细胞的培养物， 在该系统中，单个小脑颗粒神经元的定向迁移可以 在盖玻片上真实的实时观察。这种创新的文化体系 允许高分辨率定量成像和细胞内操作， 单个迁移神经元的不同细胞区域中的第二信使， 从而使我们能够直接检查第二信使的作用， 调节神经元迁移。在这项研究中，我们将具体确定 细胞内Ca2+及其时空模式如何调节 以及颗粒细胞迁移的方向， 高分辨率Ca2+成像和空间限制的光活化释放 钙离子笼。同样，我们也将确定cAMP在调节 定向细胞运动。一个常见的方案是细胞内信号， 不仅内在地调节定向细胞运动， 细胞外信号对神经元迁移的影响我们的长期目标是阐明 控制和调节年轻人迁移的细胞机制 神经元这些独特而创新的研究可以产生大量的数据， 哪些重要的未来研究可以建立，以获得重要的见解， 神经元迁移的分子和细胞机制， 这对我们理解大脑发育以及 开发潜在的治疗大脑疾病的方法， 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