Mechanisms of Purkinje cell migration

浦肯野细胞迁移机制

• 批准号: 8804825
• 负责人: Jonathan A Cooper
• 金额: $ 26.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804825
• 关键词: Address; Adoption; Autistic Disorder; Birth; Brain Part; Brain region; Cell Adhesion Molecules; Cell Communication; Cells; Cerebellum; Cerebrum; Cognition; Complex; Conflict (Psychology); Cues; DNA; DNA Sequence Rearrangement; Data; Defect; Dendrites; Development; Disease; Electroporation; Emotions; Environment; Epilepsy; Equilibrium; Fiber; Future; Gait; Gene Expression; Gene Mutation; Genetic; Goals; Growth; Human; Image; Immigration; Individual; Investigation; Label; Learning; Life; Locomotion; Maintenance; Methods; Microscopy; Movement; Mus; Muscle; Mutation; Neocortex; Neuroglia; Neurons; Paper; Phenotype; Posture; Procedures; Prosencephalon; Purkinje Cells; Radial; Reporting; Research; Research Personnel; Role; Signal Transduction; Specific qualifier value; Staging; Stereotyping; Structure; System; Testing; Textbooks; Time; Ventricular; base; cell motility; cell type; experience; genetic manipulation; granule cell; in utero; migration; motor control; motor learning; mutant; neocortical; novel; postnatal; prenatal; progenitor; public health relevance; synaptic function; synaptogenesis; ubiquitin-protein ligase; vector

 DESCRIPTION (provided by applicant): The cerebellum coordinates and synchronizes balance, movement, emotion and cognition. Cerebellar defects contribute to disorders in motor control, equilibrium, posture and learning and are frequent pathological signs in epilepsy and autism. The seeming simplicity of cerebellar structure belies its developmental complexity, with reciprocal interactions between the two principal cell types, the Purkinje cells and granule cells. The resulting cell non-autonomous effects have been an obstacle to understanding the developmental mechanisms. The textbook view has been that Purkinje cells migrate by locomotion along radial glia fibers, and absence of an environmental cue, Reelin, inhibits detachment from the radial glia. However, there are reasons to question this view. First, Purkinje cells were recently seen to move across rather than along radial glia. Second, even though Reelin regulates neuron migrations in the forebrain, it regulates glia-independent migration. In addition, we recently found that an E3 ubiquitin ligase, CRL5, regulates Purkinje cell migration, but, again, the cellular mechanism is unknown. These issues are currently difficult to address because it is challenging to genetically manipulate individual Purkinje cells and observe their migrations in a normal environment. Therefore, our immediate goal is to adapt methods to track and genetically alter Purkinje cells as they migrate and differentiate in the cerebellum. Then, we will combine these new methods with our experience studying neuron migration in the neocortex in order to address key questions of how Purkinje cells migrate and how they are regulated by Reelin and CRL5. An ancillary benefit of the proposed research is that the methods we develop will be invaluable for future investigation of pre- and post-natal cerebellar development, disease and degeneration.

 描述（由申请人提供）：小脑协调和同步平衡、运动、情绪和认知。小脑缺陷会导致运动控制、平衡、姿势和学习障碍，并且是癫痫和自闭症的常见病理症状。小脑结构看似简单，却掩盖了其发育的复杂性，两种主要细胞类型（浦肯野细胞和颗粒细胞）之间存在相互作用。 由此产生的细胞非自主效应一直是理解发育机制的障碍。教科书的观点是，浦肯野细胞通过沿着放射状神经胶质纤维运动来迁移，并且环境信号 Reelin 的缺失会抑制放射状神经胶质细胞的脱离。然而，有理由质疑这种观点。首先，最近发现浦肯野细胞穿过而不是沿着放射状胶质细胞移动。其次，尽管 Reelin 调节前脑中的神经元迁移，但它调节不依赖于神经胶质细胞的迁移。此外，我们最近发现 E3 泛素连接酶 CRL5 调节浦肯野细胞迁移，但其细胞机制仍不清楚。这些问题目前很难解决，因为对单个浦肯野细胞进行基因操作并观察它们在正常环境中的迁移具有挑战性。因此，我们的近期目标是采用方法来跟踪和遗传改变浦肯野细胞在小脑中迁移和分化的过程。然后，我们将把这些新方法与我们研究新皮质神经元迁移的经验相结合，以解决浦肯野细胞如何迁移以及它们如何受Reelin和CRL5调节的关键问题。拟议研究的一个附带好处是，我们开发的方法对于未来对产前和产后小脑发育、疾病和退化的研究具有不可估量的价值。