ROLE OF REELIN IN CONTROL OF CELL MIGRATION IN BRAIN

描述：来自天然突变研究的信息， 老鼠为我们理解 哺乳动物的发育 reeler小鼠是一种共济失调性神经发育 细胞迁移缺陷导致广泛破坏的突变体 大脑中的层状结构。 异常层状组织是 在大脑皮层、海马和小脑中明显， 在其他几个大脑区域也发现了缺陷， 核和嗅球。 解剖和生理研究 reeler认为，突变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 负责reeler突变（reelin），通过利用一个 插入诱变事件。 其蛋白质产品具有以下特点： 细胞外基质成分，它表达在时间和 在胚胎和出生后发育过程中的空间模式， 与在reeler小鼠中观察到的表型缺陷一致。 我们 初步结果表明，Reelin是一个有益的，外在的因素， 这是大脑细胞结构组织所必需的， 我认为Reelin的功能是通过与其他几个 细胞外和/或细胞表面蛋白。 我们现在打算调查 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 表达载体和对Reelin具有特异性的抗体。 这些试剂将 用于比较全长的粘附和细胞迁移特性， 并在细胞培养、脑组织移植和脑切片中发现了变异的Reelin 准备工作 在这些测定中定义的Reelin的功能结构域， 将用于使用生物化学方法鉴定Reelin结合蛋白 方法以及酵母双杂交系统。 编码Reelin的基因 结合蛋白将被分离并根据它们的 分子和生物学特性。 此外，Reelin发起人将 在转基因小鼠研究中定义并用于表达突变的Reelin 体内蛋白质 这将确定以下方面的功能贡献： 在自然环境中的特定领域。 这项建议会 阐明细胞迁移中涉及的细胞和生物化学事件 从而促进大脑正常发育 这些知识将有助于 了解几种病理条件，包括儿科 癫痫和精神分裂症。 此外，阐明机制 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.