Function of Reelin in cortical development

Reelin 在皮质发育中的作用

• 批准号: 7096924
• 负责人: GABRIELLA D'ARCANGELO
• 金额: $ 3.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096924
• 关键词: biological signal transduction; blood lipoprotein; cerebral cortex; dendrites; developmental neurobiology; gene mutation; genetically modified animals; hippocampus; laboratory mouse; microarray technology; nerve /myelin protein; neurogenesis; protein structure function; pyramidal cells; receptor; recombinant proteins; tissue /cell culture; yeast two hybrid system

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（申请人提供）：神经元迁移、成熟和连接方面的发育缺陷在人类神经系统疾病中很常见，包括癫痫、精神分裂症和智力低下。在大脑发育过程中获得适当的神经元特征对其在成人生活中的功能至关重要。然而，调控大脑发育许多方面的分子机制尚不清楚。决定大脑皮质结构细胞结构的最佳特征因子是reelin，突变型reelin小鼠的基因被破坏，在缺乏reelin蛋白的情况下，大脑发育的许多方面都异常，包括神经元迁移，导致细胞层破坏和树突发育。Reelin是一种细胞外蛋白，产生于皮层边缘层，易发生蛋白分裂。先前的研究表明，控制皮质层形成的Reelin信号是由两个细胞表面受体介导的，即极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2 (ApoER2)，以及细胞内适配器蛋白Disabled1 （Dab1）。此外，Reelin拥有一种蛋白酶活性，对大脑发育也很重要。在富含reelin的浅层中，大多数主要神经元终止迁移并形成初始树突树突。然而，目前尚不清楚Reelin是否直接调节树突生长，并且对介导其功能的细胞事件知之甚少。我们认为Reelin的功能是通过诱导细胞骨架变化来实现胚胎发育和出生后大脑树突成熟过程中正确的神经元定位。在本研究中，我们将验证Reelin直接调节海马锥体细胞树突生长的假设，并阐明介导这一功能的分子事件。将采用生物化学、遗传学、细胞生物学和分子方法的结合来检验我们的假设。重组Reelin将被纯化并进行生化表征，利用突变体和转基因小鼠在体内和体外研究海马树突发育，并通过基因筛选确定Reelin的新的下游靶点。我们的研究将有助于更好地了解Reelin在正常大脑发育中的作用。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。