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Function of Reelin in cortical development

Reelin 在皮质发育中的作用

基本信息

批准号：
7196407
负责人：
GABRIELLA D'ARCANGELO
金额：
$ 12.47万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7196407
关键词：
Address Adult Affect Affinity Binding Biochemical Biochemical Genetics Biological Assay Biology Brain Cell Surface Receptors Cells Cellular Morphology Cellular biology Cognition Disorders Conditioned Culture Media Culture Media Cytoskeleton Defect Dendrites Development Disabled Persons Disruption Embryonic Development Endopeptidases Epilepsy Event Extracellular Protein Gene Expression Genes Genetic Genetic Screening Goals Green Fluorescent Proteins Growth Hippocampus (Brain)Human In Vitro Incubated Investigation Knockout Mice LDL-Receptor Related Protein 1 Lead Length Life Lipoprotein Receptor Mediating Mediator of activation protein Mental Retardation Microarray Analysis Molecular Molecular Genetics Mus Mutation Neuronal Ectopia Neurons Pathway interactions Peptide Hydrolases Positioning Attribute Process Property Protein Isoforms Proteins Pyramidal Cells Reagent Recombinant Proteins Recombinants Reeler Mouse Role Schizophrenia Secondary to Serine Protease Signal Pathway Signal Transduction Signaling Molecule Slice Structure System Taste Perception Testing Transgenes Transgenic Mice VLDL receptor adapter protein apolipoprotein E receptor 2 cDNA Arrays in vivo inhibitor/antagonist migration mutant nervous system disorder novel postnatal protein protein interaction receptor reelin protein research study stable cell line yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Developmental defects in neuronal migration, maturation and connectivity are commonly found in human neurological diseases including epilepsy, schizophrenia and mental retardation. The acquisition of appropriate neuronal features during brain development is crucial for its function in adult life. However, the molecular mechanisms that regulate many aspects of brain development are poorly understood. The best characterized factor that determines the cytoarchitecture of cortical brain structures is reelin, the gene disrupted in the mutant reeler mouse, in the absence of the Reelin protein, many aspects of brain development are abnormal including neuronal migration, leading to the disruption of cellular layers, and dendrite development. Reelin is an extracellular protein produced in cortical marginal layers and subject to proteotytic cleavage. It was previously demonstrated that the Reelin signal that controls cortical layer formation is mediated by two cell surface receptors, the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), and by the intracellular adapter protein Disabled1 (Dab1). In addition, Reelin possesses a protease activity that could also be important for brain development. In superficial Reelin-rich layers, most principal neurons terminate their migration and develop an initial dendritic arborization. However, it is unclear whether Reelin directly regulates dendrite growth and little is known about the cellular events that mediate its function. We propose that Reelin functions by inducing cytoskeletal changes that enable correct neuronal positioning during embryonic development and dendrite maturation in the postnatal brain. In this proposal, we will test the hypothesis that Reelin directly regulates the growth of hippocampal pyramidal cell dendrites and elucidate the molecular events that mediate this function. A combination of biochemical, genetic, cell biology and molecular approaches will be taken to test our hypothesis. Recombinant Reelin will be purified and characterized biochemically, hippocampal dendrite development will be studied in vivo and in vitro using mutant and transgenic mice, and novel downstream targets of Reelin will be identified by genetic screens. Our studies will lead to a better understanding of Reelin function in normal brain development. Furthermore, our findings may have significant implications for cognitive disorders associated with Reelin deficiency.

描述（由申请人提供）：在人类神经系统疾病（包括癫痫、精神分裂症和精神发育迟滞）中常见神经元迁移、成熟和连接的发育缺陷。在大脑发育过程中获得适当的神经元特征对于其在成年生活中的功能至关重要。然而，调节大脑发育许多方面的分子机制却知之甚少。决定皮质脑结构的细胞结构的最佳表征因子是Reelin，该基因在突变型Reeler小鼠中被破坏，在不存在Reelin蛋白的情况下，脑发育的许多方面是异常的，包括神经元迁移，导致细胞层的破坏和树突发育。Reelin是在皮质边缘层中产生的细胞外蛋白，并且受到蛋白水解切割。先前证明，控制皮质层形成的Reelin信号由两种细胞表面受体介导，即极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER 2），以及细胞内衔接蛋白Disabled1（Dab1）。此外，Reelin具有蛋白酶活性，这对大脑发育也很重要。在表层的Reelin丰富的层，大多数主要神经元终止其迁移，并开发一个初始的树突状分支。然而，目前还不清楚是否Reelin直接调节树突的生长和鲜为人知的细胞事件，介导其功能。我们建议，Reelin功能诱导细胞骨架的变化，使正确的神经元定位在胚胎发育和树突成熟的出生后的大脑。在这个建议中，我们将测试的假设，Reelin直接调节海马锥体细胞树突的生长，并阐明介导这一功能的分子事件。生物化学，遗传学，细胞生物学和分子方法的组合将被用来测试我们的假设。重组Reelin将被纯化和生化表征，海马树突发育将在体内和体外研究使用突变和转基因小鼠，和新的下游靶标Reelin将被确定的遗传筛选。我们的研究将导致更好地了解Reelin在正常大脑发育中的功能。此外，我们的研究结果可能对与Reelin缺乏相关的认知障碍具有重要意义。