MOLECULAR INTERACTIONS IN CEREBELLAR GRANULE NEURON

描述(改编自申请人的摘要)：本报告的目标 应用是理解构成地层的分子信号 细胞结构在小脑发育中的作用。在过去的几年里， 已有多项研究涉及细胞黏附/识别分子 神经系统中的免疫球蛋白基因超家族。然而，研究表明 关于这些分子在体内神经发育中的功能的研究很少， 以及对它们在建立神经元结构中的作用的理解 在很大程度上仍然难以捉摸。当前的应用程序将解决 小脑发育中的IgSF细胞黏附/识别分子接触蛋白 采用体内和体外相结合的方法。几行 有证据表明，接触蛋白在调节细胞周期中起着关键作用。 控制小脑发育的相互作用。这位调查员已经 产生了接触蛋白基因功能中断的小鼠，这些小鼠发展为严重的 共济失调表型，开始于出生后第9天。这种突变是致命的 出生后第18天。对突变的小脑的初步分析已经确定 颗粒神经元发育缺陷。这个神经元群体，在 野生型，在出生后小脑发育过程中表达接触蛋白， 为研究接触蛋白在神经中的作用提供了一个合适的模型 发展。本项目将重点介绍Contact的两个主要功能，即 来自对基因敲除小鼠的初步分析。首先，使用 基因敲除小鼠，研究人员已经获得了接触蛋白作用的证据 在调节外胚内颗粒细胞前体的数量上 层(EGL)。该项目将测试几个假设，这些假设将解决以下问题 接触蛋白介导的细胞相互作用是增殖所必需的， 颗粒神经元未分化状态的存活和/或维持 EGL中的前体。其次，更多的初步数据显示， 接触蛋白在大鼠脑内平行纤维轴突成束中的作用 小脑分子层。调查员提议调查 Contactin调节这一功能的机制，并将在 体外接触蛋白与控制轴突的配体相互作用 互动。这些研究将推动对 小脑发育的分子基础，尤其是提供了 剖析IgSF细胞黏附/识别功能的机会 生物环境中的分子。因此，这项工作可能会为以后的工作提供借鉴 对一系列相似蛋白质的研究。

DESCRIPTION (Adapted from the applicant's abstract): The goal of this application is to understand the molecular signals that underlie the formation of cytoarchitecture in cerebellar development. Over the past few years, a number of studies have addressed cell adhesion/recognition molecules of the immunoglobulin gene superfamily (IgSF) in the nervous system. However, studies on the function of these molecules in neural development in vivo are sparse, and the understanding of their roles in establishing neuronal architecture remains largely elusive. The current application will address the role of the IgSF cell adhesion/recognition molecule contactin in cerebellar development using a combination of in vivo and in vitro approaches. Several lines of evidence indicate that contactin plays a pivotal role in regulating cellular interactions that control cerebellar development. This investigator has generated mice with disrupted contactin gene function which develop a severely ataxic phenotype with an onset of postnatal day 9. The mutation is lethal by postnatal day 18. Preliminary analyses of the mutant cerebellum have identified defects in granule neuron development. This neuron population, which, in the wild type, expresses contactin throughout postnatal cerebellar development, provides an opportune model to study the role of contactin in neural development. This project will focus on two major functions of contactin that are indicated from preliminary analyses of the knockout mice. First, using the knock-out mice, the investigator has obtained evidence for a role of contactin in regulating the number of granule cell precursors in the external germinal layer (EGL). The project will test several hypotheses, which will address if contactin-mediated cellular interactions are required for the proliferation, survival and/or maintenance of the undifferentiated state of granule neuron precursors in the EGL. Second, additional preliminary data have revealed a later role of contactin in the fasciculation of parallel fiber axons in the cerebellar molecular layer. The investigator proposes to investigate the mechanism by which contactin regulates this function, and will determine in vitro the ligands with which contactin interacts in controlling axon-axon interactions. These studies will move forward the understanding of the molecular basis of cerebellar development, and, in particular, provide an opportunity to dissect the function of an IgSF cell adhesion/recognition molecule in a biological setting. Thus, this work may set an example for future studies on a host of similar proteins.