PROTEOGLYCANS AND BRAIN DEVELOPMENT

蛋白聚糖与大脑发育

基本信息

批准号：
2635698
负责人：
Arthur D Lander
金额：
$ 30.31万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-04-01 至 2005-03-31
项目状态：
已结题

项目摘要

Cell surface heparan sulfate proteoglycans (HSPGs) are abundant, ubiquitous molecules, that bind via heparan sulfate (HS) chains to growth factors, extracellular matrix proteins, and other important cellular effectors. The major cell surface HSPGs are products of two gene families: the syndecans, which are transmembrane proteins, and the glypicans, which are glycosylphosphatidylinositol-anchored. Four syndecans and at least five glypicans are expressed in mammals, including man. The biological functions of cell surface HSPGs are poorly understood, but at least one function involves regulation of the responses of cells to polypeptide growth factors. Recently, a human birth defects syndrome associated with dysregulated tissue growth was shown to be caused by null mutations in glypican-3. Genetic studies in the fruitfly, Drosophila, have also linked loss of glypican function to defects in tissue growth and patterning. One tissue in which glypicans are likely to play especially important development roles is the nervous system. Experiments with cultured neutral cells and lower organisms have long pointed to crucial roles for HSPGs in neutral patterning, axon guidance, and synapse formation. Previous work on this project has demonstrated that glypicans-1 and -2 are among the most abundant HSPGs in the mammalian brain, and are expressed in locations such as neutral precursor zones, growing axons, and synaptic terminal fields, that are consistent with playing such developmental roles. The goals for the next project period focus on uncovering the functions of glypicans-1 and -2 in the mammalian nervous system, and on relating glypican function to structural features of the glypicans, such as the presence of HS chains, the mode of membrane anchorage, and presence of a large N- terminal globular domain that does not carry HS, yet has been highly conserved throughout evolution. Functional experiments involve the analysis of mice engineered to lack glypican-1, glypican-2, or both. Glypican-2 null mice have already been made, and the generation of glypican-1 null mice is in progress. Analysis of structure-function relationships in glypicans will use the fruitfly as an experimental system in which genes encoding altered glypicans can be rapidly and quantitatively tested for function. Finally, the results of observing mutant phenotypes and making structure/function correlations will be used to direct a genetic and biochemical search for the ligands with which glypicans interact in mammalian nervous system development. These studies should provide insights into how an important and poorly understood class of molecules regulates basic developmental processes, particularly in the nervous system.

细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）丰富，普遍存在的分子，通过硫酸乙酰肝素 (HS) 链结合生长因子、细胞外基质蛋白和其他重要的细胞效应器。主要的细胞表面 HSPG 是两种物质的产物基因家族：多配体（syndecans），它们是跨膜蛋白，以及磷脂酰肌醇蛋白聚糖，是糖基磷脂酰肌醇锚定的。四多糖蛋白聚糖和至少五种磷脂酰肌醇蛋白聚糖在哺乳动物中表达，包括男人。细胞表面HSPGs的生物学功能较差理解，但至少有一项功能涉及调节细胞对多肽生长因子的反应。最近，一个人类与组织生长失调相关的出生缺陷综合征表明是由磷脂酰肌醇蛋白聚糖 3 的无效突变引起的。遗传学研究果蝇，果蝇，也将磷脂酰肌醇蛋白聚糖功能的丧失与组织生长和图案形成的缺陷。含有磷脂酰肌醇蛋白聚糖的一种组织可能在发展中发挥特别重要的作用的是神经系统。用培养的中性细胞和低等生物进行的实验长期指出 HSPG 在中性模式、轴突中的关键作用引导和突触形成。该项目之前的工作有证明磷脂酰肌醇蛋白聚糖-1和-2是最丰富的HSPG之一在哺乳动物大脑中，并在中性等位置表达前体区、生长轴突和突触末端区，与扮演这种发展角色相一致。的目标下一个项目期间的重点是揭示 glypicans-1 和 -2 在哺乳动物神经系统中，以及与磷脂酰肌醇蛋白聚糖功能相关磷脂酰肌醇蛋白聚糖的结构特征，例如 HS 的存在链、膜锚定模式以及大N-的存在末端球状结构域不携带 HS，但已被高度在整个进化过程中保守。功能实验涉及分析被改造为缺乏磷脂酰肌醇蛋白聚糖-1、磷脂酰肌醇蛋白聚糖-2或两者的小鼠。 Glypican-2缺失小鼠已经被制备出来，并产生了 glypican-1 缺失小鼠正在进行中。结构功能分析磷脂酰肌醇蛋白聚糖的关系将使用果蝇作为实验系统中，编码改变的磷脂酰肌醇蛋白聚糖的基因可以快速且定量测试功能。最后是观察结果突变表型和结构/功能相关性将是用于指导配体的遗传和生化搜索磷脂酰肌醇蛋白聚糖在哺乳动物神经系统发育中相互作用。这些研究应该提供关于重要的和糟糕的已知的分子类别调节基本的发育过程，特别是在神经系统中。