MOLECULAR INTERACTIONS IN CEREBELLAR GRANULE NEURON

描述（改编自申请人的摘要）：本研究的目标 应用是了解形成的分子信号 小脑发育中的细胞结构在过去的几年里，A 许多研究已经解决了细胞粘附/识别分子的 免疫球蛋白基因超家族（IgSF）在神经系统中的作用。然而研究 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作用的理解 仍然很难找到当前应用程序将解决 IgSF细胞粘附/识别分子接触在小脑发育中作用 使用体内和体外方法的组合。几行 有证据表明，接触在调节细胞 控制小脑发育的相互作用这位调查员 产生了接触蛋白基因功能被破坏的小鼠， 出生后第9天开始出现共济失调表型。突变是致命的， 出生后第18天。对变异小脑的初步分析表明 颗粒神经元发育缺陷。这个神经元群体， 野生型，在整个出生后小脑发育中表达接触蛋白， 提供子一个合适模型来研究接触在神经系统中作用 发展这个项目将集中在联系两个主要功能上， 从敲除小鼠的初步分析中可以看出。首先利用 在基因敲除小鼠中，研究者已经获得了接触 调节外胚层颗粒细胞前体细胞的数量 层（EGL）。该项目将测试几个假设，这将解决如果 增殖需要接触素介导的细胞相互作用， 存活和/或维持颗粒神经元的未分化状态 前体在EGL。第二，额外的初步数据显示， 接触在平行纤维轴突成束中的后期作用 小脑分子层调查员建议调查 接触调节这一功能机制，并将决定 在体外，与接触素相互作用的配体控制轴突-轴突 交互.这些研究将推进对 小脑发育的分子基础，特别是，提供了一个 剖析IgSF细胞粘附/识别功能的机会 分子在生物学环境中的作用。因此，这项工作可以为今后的工作树立一个榜样。 对大量相似蛋白质的研究。

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.