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：
6446640
负责人：
WILLIAM J BRUNKEN
金额：
$ 14.71万
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（逐字摘自申请人的摘要）：层粘连蛋白是作为细胞粘附分子的生物活性分子，规范发展各方面，稳定复杂局面解剖结构。它们是大的细胞外基质分子由三个亚基链组成，分别称为α、β和γ。五个阿尔法，已鉴定出三个β链和三个γ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）； β2 链减少 Walker-Warburg 综合征和一组复杂的中枢神经系统发育障碍（肌肉-脑-眼疾病；色素性视网膜炎伴耳聋（RP21 伴耳聋）耳聋）； Walker-Warburg 综合征）映射到 gamma3 基因的位点。层粘连蛋白在中枢神经系统中广泛表达；我们已经证明，在人类、大鼠中，牛和小鼠视网膜，四个层粘连蛋白链（α3、α4、β2 和 gamma3）存在于光感受器间基质和外部光感受器基质中丛状层（OPL）。这些链可能形成两个异源三聚体，层粘连蛋白-13 和层粘连蛋白-14。视网膜层粘连蛋白链似乎发挥着重要作用在光感受器形态发生中的作用；首先，这些链被表达在视杆细胞发生之前并持续到成年期；二、消融编码其中一条链 beta2 的基因的突变导致产生具有异常功能的畸形光感受器。具体来说，光感受器外部段的长度减少； OPL 中的感光终端是被破坏：最后，在 ERG 中，b 波的幅度急剧变化减少，表明光感受器和双极之间的传输细胞因层粘连蛋白β2链功能丧失而受到破坏。我们假设层粘连蛋白-13 和-14 是突触形成的关键介质 OPL 中光感受器和二级细胞之间的稳定性。此外，我们假设层粘连蛋白-13 和-14 形成独特的底物光感受器轴突与光感受器轴突相互作用并粘附在光感受器轴突上，以便精细的突触，最后，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。我们提议检验该假设的几个方面。我们会问几个具体问题：（1）时空表达是什么层粘连蛋白结合分子位于 OPL 中； (2)这些分子是否介导细胞与 OPL 层粘连蛋白的结合； (3) 解剖学和生理学光感受器突触的改变是由层粘连蛋白基因破坏引起的。