Mechanisms of Purkinje cell migration

浦肯野细胞迁移机制

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：小脑坐标并同步平衡，运动，情感和认知。小脑缺陷会导致运动控制，平衡，姿势和学习的疾病，并且经常是癫痫和自闭症的病理体征。小脑结构的看似简单性掩盖了其发育复杂性，两种主要细胞类型之间的相互作用，即purkinje细胞和颗粒细胞。由此产生的细胞非自主效应一直是了解发育机制的障碍。教科书的观点是，浦肯野细胞通过沿着径向神经胶质纤维的运动迁移，并且没有环境提示，即reelin，抑制了从radial胶质神经胶质的脱离。但是，有理由质疑这种观点。首先，最近看到浦肯野细胞在跨径向神经胶质细胞中移动。其次，即使reelin调节前脑中的神经元迁移，它也调节了与神经胶质无关的迁移。此外，我们最近发现，E3泛素连接酶CRL5调节Purkinje细胞迁移，但同样，细胞机制是未知的。这些问题目前很难解决，因为它挑战了基因操纵单个purkinje细胞并在正常环境中观察其迁移。因此，我们的近期目标是适应方法，以跟踪和一般改变Purkinje细胞在小脑中迁移和区分时。然后，我们将将这些新方法与研究新皮层中神经元迁移的经验相结合，以解决珀肯吉细胞如何迁移以及如何通过reelin和crl5调节它们的关键问题。拟议的研究的辅助好处是，我们开发的方法将有效地对产前和产后小脑发育，疾病和变性的未来投资有效。