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：
6384826
负责人：
WILLIAM J BRUNKEN
金额：
$ 27.74万
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 2003-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (Verbatim from applicant's abstract): Laminins are biologically-active molecules which function as cell adhesion molecules, regulate various aspects of development, and serve to stabilize complex anatomical structures. They are large extracellular matrix molecules that are composed of three subunit chains, designated alpha, beta and gamma. Five alpha, three beta and three gamma chains have been identified. 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) map to the site of the gamma3 gene. Laminins are widely expressed in the CNS; we have shown that in the human, rat, bovine and mouse retina, four laminin chains (alpha3, alpha4, beta2 and gamma3) are found in the interphotoreceptor matrix and in the matrix of the outer plexiform layer (OPL). These chains are likely to form two heterotrimers, laminin-13 and laminin-14. The retinal laminin chains 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 chains, beta2, results in the production of dysmorphic photoreceptors with aberrant function. Specifically, photoreceptor outer segments are reduced in length; the photoreceptor terminal in the OPL are disrupted: finally, in ERGs, the amplitude of the b-wave is drastically diminished, suggesting that transmission between photoreceptors and bipolar cells is disrupted by loss of laminin beta2 chain function. We hypothesize that laminins-13 and -14 are critical mediators of synapse formation and stabilization between photoreceptors and second order cells in the OPL. Furthermore, we hypothesize that laminins-13 and -14 form unique substrates with which photoreceptor axons interact and to which they adhere in order to elaborate synapses, and, finally, that the molecular structure of the synapse is dependent on the interactions between these laminins and their receptors. We propose to test several aspects of this hypothesis. We will ask several specific questions: (1) what the spatial and temporal expression of laminin-binding molecules is in the OPL; (2) whether these molecules mediate the binding of cells to OPL laminins; and (3) what anatomical and physiological alterations in the photoreceptor synapse result from laminin gene disruptions.

描述（逐字研究来自申请人的摘要）：层粘连蛋白是充当细胞粘附分子的生物活性分子，调节发展的各个方面，并有助于稳定复杂解剖结构。它们是大的细胞外基质分子由三个亚基链组成，分别为Alpha，Beta和Gamma。五个alpha，已经确定了三个β和三个伽马链。几种疾病神经系统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）； beta2链减少 Walker-Warburg综合征和一组复杂的CNS发育障碍（肌肉 - 脑眼部疾病；色素性视网膜炎和耳聋（RP21）耳聋）; Walker-Warburg综合征）地图到GAMMA3基因的位点。层粘连蛋白在中枢神经系统中广泛表达；我们已经表明，在人的老鼠中牛和小鼠视网膜，四个层粘连蛋白链（alpha3，alpha4，beta2和gamma3）在photoreceptor矩阵和外部基质中发现丛状层（OPL）。这些链可能形成两个异三聚体，层粘连蛋白13和层粘连蛋白14。视网膜层粘连蛋白链看起来很重要在光感受器的形态发生中的作用；首先，这些链被表达在rod创世纪发作之前，一直持续到成年。第二，消融编码其中一个链的基因beta2导致产生具有异常功能的畸形感受器。具体而言，光感受器外部段的长度减小； OPL中的光感受器端子为被破坏了：最后，在ERG中，B波的幅度很大减少，表明光感受器和双极细胞因层粘连蛋白β2链功能的丧失而破坏。我们假设这一点层粘连蛋白13和-14是突触形成的关键介体， OPL中的光感受器和二阶细胞之间的稳定化。此外，我们假设层粘连蛋白13和-14形成独特的底物与哪些光感受器轴突相互作用以及它们粘附在于精心制作的突触，最后是突触的分子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。我们会问几个特定问题：（1）什么空间和时间表的表达层粘连蛋白结合分子在OPL中；（2）这些分子是否介导细胞与OPL层粘连蛋白的结合；（3）什么解剖学和生理学光感受器突触的改变导致层粘连蛋白基因破坏。