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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6384826
• 关键词: animal tissue; central nervous system; confocal scanning microscopy; electrophysiology; extracellular matrix; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; laminin; organ culture; protein structure function; receptor binding; retina; retina degeneration; retinal bipolar neuron; rod cell; synaptogenesis; visual photoreceptor

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（来自申请人摘要的逐字描述）：层粘连蛋白是 起细胞粘附分子作用的生物活性分子， 规范发展的各个方面，并服务于稳定复杂的 解剖结构它们是大的细胞外基质分子， 由三条亚基链组成，分别命名为α、β和γ。阿尔法5号， 已经鉴定了三个β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α 2链（裂球蛋白）; β 2链减少， 沃克-沃伯格综合征和一组复杂的中枢神经系统发育障碍 （肌-脑-眼疾病;视网膜色素变性伴耳聋（RP 21伴 耳聋）;沃克-沃伯格综合征）映射到γ 3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，在人类，大鼠， 牛和小鼠视网膜，四条层粘连蛋白链（α 3、α 4、β 2和γ 3） 存在于感光细胞间基质和外膜基质中 网状层（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在 在光感受器的形态发生中的作用;首先，这些链被表达 在视杆细胞发生之前，并持续到成年期;第二，消融 编码β 2链的基因的突变， 具有异常功能的畸形光感受器。特别是感光细胞 外节的长度减少; OPL中的感光末梢 中断：最后，在ERG中，b波的振幅急剧下降， 减少，表明光感受器和双极之间的传输 细胞由于层粘连蛋白β 2链功能的丧失而被破坏。我们假设 层粘连蛋白-13和-14是突触形成的关键介质， 光感受器和OPL中的二级细胞之间的稳定。 此外，我们假设层粘连蛋白-13和-14形成独特的底物， 光感受器轴突与其相互作用并粘附于其上， 最后，突触的分子结构 依赖于这些层粘连蛋白和它们的受体之间的相互作用。我们 我想测试这个假设的几个方面。我们会问几个 具体问题：（1）空间和时间的表达 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;以及（3）解剖学和生理学上 光感受器突触的改变是由层粘连蛋白基因破坏引起的。