Extracellular matrix in synapse formation in the CNS

中枢神经系统突触形成中的细胞外基质

基本信息

批准号：
7087782
负责人：
WILLIAM J BRUNKEN
金额：
$ 10.37万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2006-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Laminins are biologically active molecules that function as cell adhesion molecules, regulate various aspects of development, and serve to stabilize complex anatomical structures. They are large extracellular matrix molecules which are composed of three subunit chains, designated alpha, beta and gamma. Five alpha, three beta and three gamma chains have been identified. Laminins are widely expressed in the CNS; as are their receptors. Several disorders of the nervous system are linked to laminin genes: some congenital muscular dystrophies involve the alpha2 chain (merosin); the beta2 chain is reduced in Walker-Warburg syndrome; and a complex group of CNS developmental disorders (muscle-brain-eye disease; retinitis pigmentosa with deafness (RP21 with deafness); Walker-Warburg syndrome) maps to the site of the gamma3 gene. Genetic disruptions in some laminin-related genes also result in human disease and in dysmorphogenesis in animal models. We have identified two novel CNS laminins, alpha4beta2gamma3 and alpha5beta2gamma3 (LN 14 & LN 15, respectively); these are found in the interphotoreceptor matrix and in the matrix of the outer plexiform layer (OPL). These laminins appear to play important roles in the morphogenesis of photoreceptors. First, these chains are expressed prior to the onset of rod genesis and persist into adulthood. Second, ablation of the gene encoding one of the beta2 chains results in the production of dysmorphic photoreceptors; specifically, photoreceptor outer segments are reduced in length and the photoreceptor terminals in the OPL are disrupted. Finally the amplitude of the ERG b-wave is drastically diminished suggesting that transmission from photoreceptors to second order cells is disrupted by loss of beta2-containing laminins. We hypothesize that LN 14 and 15 are critical mediators of synapse assembly and stabilization. Furthermore, we hypothesize that LN14 and 15 form unique substrates with which photoreceptor terminals interact. Specifically, we hypothesize that the molecular assembly and structure of the photoreceptor synapse is dependent on the interactions between these laminins and their receptors. We propose to test several aspects of this hypothesis. We will ask two specific questions: 1) What is the functional composition of the laminin complex in the OPL? 2) How does disruption of the laminin complex alter the functional organization of the OPL? With these studies, we will: gain insight into the molecular mechanisms of synaptic assembly in the outer retina; define the role of the ECM in this process; and shed light on the basis of a series of genetic disorders in humans.

描述（由申请人提供）：层粘连蛋白是具有生物活性的分子，可作为细胞粘附分子，调节发育的各个方面，并有助于稳定复杂的解剖结构。它们是大型细胞外基质分子，由三个亚基链组成，分别是指定的alpha，beta和伽马。已经确定了五个alpha，三个β和三个伽马链。层粘连蛋白在中枢神经系统中广泛表达；他们的受体也是如此。神经系统的几种疾病与层粘连蛋白基因有关：一些先天性肌肉营养不良涉及α2链（Merosin）； Walker-Warburg综合征减少了Beta2链。以及一组复杂的CNS发育障碍（肌肉 - 脑眼疾病；具有耳聋的视网膜炎色素炎（带有耳聋的RP21）； Walker-Warburg综合征）映射到Gamma3基因的位点。某些层粘连蛋白相关基因的遗传破坏也导致人类疾病和动物模型中的畸形发生。我们已经确定了两种新型的CNS层粘连蛋白，Alpha4beta2gamma3和alpha5beta2gamma3（分别为ln 14＆ln 15）；这些发现在photoreceptor矩阵和外丛状层（OPL）的基质中。这些层粘连蛋白似乎在光感受器的形态发生中起重要作用。首先，这些链是在杆创世纪发作之前表达的，并持续到成年。其次，编码β2链之一的基因的消融导致产生畸形感光体。具体而言，光感受器的外部段的长度减小，并且OPL中的光感受器端子被破坏。最后，ERG B波的幅度大大减少，这表明从感光体到二阶细胞的传播被含有β2的层粘连蛋白的丢失而破坏。我们假设LN 14和15是突触组装和稳定的关键介体。此外，我们假设LN14和15形成了光感受器终端相互作用的独特底物。具体而言，我们假设光感受器突触的分子组装和结构取决于这些层粘连蛋白及其受体之间的相互作用。我们建议检验该假设的几个方面。我们将提出两个具体问题：1）OPL中层粘连蛋白复合物的功能组成是什么？ 2）层粘连蛋白复合物的破坏如何改变OPL的功能组织？通过这些研究，我们将：深入了解外视网膜中突触组件的分子机制；定义ECM在此过程中的作用；并根据人类的一系列遗传疾病来阐明。