ROLE OF REELIN IN CONTROL OF CELL MIGRATION IN BRAIN

描述：来自对自然发生突变的研究的信息 鼠标对我们理解 哺乳动物的发育。卷轴老鼠是一种共济失调的神经发育 一种突变体，在细胞迁移过程中存在缺陷，导致广泛干扰 大脑中的层状结构。异常的层状组织是 明显存在于大脑皮层、海马体和小脑以及其他 包括橄榄核在内的其他几个大脑区域也有缺陷。 核团和嗅球。颈椎的解剖学和生理学研究 Reeler认为这种突变会影响有丝分裂后神经元的能力 在发育中的大脑中占据正确的位置。我们分离出了这个基因 对卷轴突变(卷轴)负责的人 插入突变事件。其蛋白质产品具有以下特点 细胞外基质成分，它在时间和时间上表达 胚胎和出生后发育的空间格局，即 与在卷线鼠身上观察到的表型缺陷一致。我们的 初步结果表明，Reelin是一个具有启发性的外在因素。 这是大脑的细胞结构组织所必需的，我们 建议Reelin通过与其他几个 胞外和/或细胞表面蛋白。我们现在打算调查 了解Reelin的功能和表达调控以了解其作用 在控制哺乳动物的分子和细胞事件中 神经发育。作为分析的第一步，我们将准备 Reelin特异性表达载体和抗体。这些试剂会 用来比较全长细胞的黏附和细胞迁移特性 并在细胞培养、脑外植体和脑片中突变Reelin 准备工作。在这些检测中定义的Reelin的功能结构域， 将用于通过生化手段鉴定Reelin结合蛋白 方法以及酵母双杂交系统。编码卷轴的基因 结合蛋白将被分离出来，并根据它们的 分子和生物学特性。此外，Reelin发起人将 在转基因小鼠研究中被定义并用于表达突变的Reelin 体内的蛋白质。这将确立以下功能贡献 Reelin在自然环境中的特定结构域。这项提议将 阐明与细胞迁移有关的细胞和生化事件 这会导致正常的大脑发育。这些知识将有助于 了解几种病理情况，包括儿科 癫痫和精神分裂症。此外，还阐明了其作用机制。 负责细胞迁移是控制肿瘤侵袭的关键 和转移，特别是在大脑中。

DESCRIPTION: Information from the study of naturally-occurring mutations in the mouse has made significant contributions to our understanding of mammalian development. The reeler mouse is an ataxic neurodevelopmental mutant that has a defect in cell migration resulting in extensive disruption of laminar structures in the brain. Aberrant laminar organization is apparent in the cerebral cortex, hippocampus and cerebellum and additional defects are seen in several other brain regions including the olivary nucleus and the olfactory bulb. Anatomical and physiological studies of reeler suggest that the mutation affects the ability of postmitotic neurons to assume correct positions in the developing brain. We isolated the gene responsible for the reeler mutation (reelin) by taking advantage of an insertional mutagenesis event. Its protein product has features of extracellular matrix components and it is expressed in a temporal and spatial pattern during embryonic and postnatal development that is consistent with the phenotypic defects observed in reeler mice. Our preliminary results suggest that Reelin is an instructive, extrinsic factor that is required for the cytoarchitectonic organization of the brain and we propose that Reelin functions by interacting with several other extracellular and/or cell surface proteins. We now intend to investigate the function and regulation of expression of Reelin to understand its role in the molecular and cellular events that control mammalian neurodevelopment. As a first step in this analysis, we will prepare expression vectors and antibodies specific for Reelin. These reagents will be used to compare the adhesion and cell migration properties of full length and mutated Reelin in cell culture, brain explants and brain slice preparations. The functional domains of Reelin, defined in these assays, will be used to identify Reelin binding proteins using biochemical approaches as well as the yeast two hybrid system. Genes encoding Reelin binding proteins will be isolated and characterized in terms of their molecular and biological properties. In addition, the reelin promoter will be defined in transgenic mouse studies and used to express mutated Reelin proteins in vivo. This will establish the functional contribution of specific domains of Reelin in a natural context. This proposal will illuminate the cellular and biochemical events involved in cell migration that lead to normal brain development. This knowledge will contribute to an understanding of several pathological conditions, including pediatric epilepsy and schizophrenia. Furthermore, elucidation of the mechanisms responsible for cell migration is critical for the control of tumor invasion and metastasis, particularly in the brain.