Multifunctional roles for doublecortin (DCX)in neural development

双皮质素 (DCX) 在神经发育中的多功能作用

基本信息

批准号：
8700554
负责人：
Bettina R Winckler
金额：
$ 34.46万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700554
关键词：
Alleles Area Attention Axon Binding Biological Assay Brain Cell Adhesion Cell Adhesion Molecules Cell physiology Cell surface Cells Cellular Membrane Cerebral cortex Clathrin Clathrin Adaptors Complex Cortical Malformation Cytoskeletal Modeling Data Defect Dendrites Development Disease Dynamin Electroporation Embryo Endocytosis Endocytosis Pathway Ensure Epilepsy Future Genes Genetic Goals Grant Growth Health Heart Human Immigration Impairment Individual Intractable Epilepsy Knock-out Lead Link Mediating Membrane Protein Traffic Membrane Proteins Mental Retardation Microtubules Molecular Morphogenesis Morphology Mus Mutation Neurodevelopmental Disorder Neurons Newborn Infant Pathway interactions Patients Phenotype Play Positioning Attribute Process Proteins Publishing RNA Interference Rattus Regulation Research Resistance Role Route Signal Transduction Surface Synapses Testing Therapeutic Intervention Time Work adhesion receptor axon growth axon guidance base cell type cognitive function knock-down lissencephaly malformation migration mutant nervous system disorder neurodevelopment neurofascin newborn neuron novel public health relevance receptor research study tool trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Wiring the brain is a complex neurodevelopmental process. When it goes wrong, human neurological disorders can arise with deficiencies ranging from mild to severe. Genes associated with such disorders are important avenues for research because they provide an entry point into understanding the molecular mechanisms of both neurodevelopmental processes and diseases. Some neurological disorders are linked genetically to genes ubiquitously expressed in many cell types whereas others are linked to neurally expressed genes. The X-linked gene doublecortin (DCX) is only expressed in neurons and is a major genetic locus for type I lissencephaly, a neurodevelopmental defect causing mental retardation and untractable epilepsy. Unraveling the molecular and cellular functions of DCX, therefore, not only has significance for advancing our understanding of DCX function in development and the disease mechanisms of Lissencephaly, but more generally advances our conceptualization of which proteins in particular are required to make a neuron and wire the brain. This grant thus goes to the heart of understanding cell-type specific mechanisms for making functional neurons and building functional circuits. The molecular and cellular roles of DCX are still incompletely understood. Much work has focused on the microtubule-binding ability of DCX, and the phenotypes associated with DCX mutations are postulated to be due to microtubule-related defects. Patient alleles of DCX are powerful tools to direct our attention to residues in DCX that are important for normal function. Surprisingly, microtubule defects have not been established for most DCX mutations, and it is thus an open question whether all cellular roles of DCX require microtubule binding. Many additional binding partners, such as the cell adhesion molecule neurofascin and clathrin adaptors, have in fact been identified for DCX, but the roles of these other interacting partners are currently not understood. In preliminary experiments, we have identified a novel function of DCX, namely endocytosis of neurofascin. Surprisingly, DCX-mediated endocytosis of neurofascin does not require microtubule binding by DCX in a PC12 assay. We will test the hypothesis that DCX plays roles in multiple cellular processes, including endocytosis, via separable molecular interactions. The objective of this proposal is to uncover the contributions of DCX-mediated endocytosis in neurodevelopment, including migration, axon growth and guidance and dendrite growth.

描述（由申请人提供）：布线是一个复杂的神经发育过程。当出错时，人类神经系统疾病可能会因轻度到重度的缺陷而出现。与此类疾病相关的基因是研究的重要途径，因为它们为理解神经发育过程和疾病的分子机制提供了一个切入点。某些神经系统疾病遗传与多种细胞类型表达的基因有关，而另一些与神经表达的基因相关。 X连锁的基因双铁蛋白（DCX）仅在神经元中表达，并且是I型Lissencephaly的主要遗传基因座，这是一种神经发育缺陷，导致智力低下和无法提取的癫痫病。因此，阐明DCX的分子和细胞功能，不仅在促进我们对DCX在发育中的理解和Lissencephaly的疾病机制方面具有重要意义，而且更普遍地提高了我们对哪些蛋白质尤其需要进行神经元和导线的概念化。因此，这项赠款是理解细胞类型的特定机制的核心，以制造功能性神经元和构建功能电路。 DCX的分子和细胞作用仍未完全理解。许多工作集中在DCX的微管结合能力上，并且假定与DCX突变相关的表型是由于微管相关的缺陷。 DCX的患者等位基因是将我们的注意力引向DCX中对正常功能很重要的残留物的强大工具。令人惊讶的是，对于大多数DCX突变，微管缺陷尚未建立，因此，DCX的所有细胞作用是否都需要微管结合。实际上，在DCX中已经确定了许多其他其他结合伴侣，例如细胞粘附分子神经蛋白和网格蛋白适配器，但是目前尚不了解这些其他相互作用伴侣的作用。在初步实验中，我们已经确定了DCX的新功能，即神经胶质素的内吞作用。出乎意料的是，DCX介导的神经胶质素的内吞作用不需要DCX在PC12分析中结合微管。我们将通过可分离的分子相互作用来检验DCX在包括内吞作用在内的多个细胞过程中起作用的假设。该提案的目的是发现神经发育中DCX介导的内吞作用的贡献，包括迁移，轴突生长和指导和树突生长。