PROTEOGLYCANS AND BRAIN DEVELOPMENT

蛋白聚糖与大脑发育

基本信息

批准号：
6539680
负责人：
Arthur D Lander
金额：
$ 32.72万
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，无处不在的分子，通过硫酸乙酰肝素（HS）链结合到生长因子，细胞外基质蛋白和其他重要细胞效应子。主要的细胞表面HSPG是两个的产物基因家族：syndecan，是跨膜蛋白， Glypicans，是糖基磷脂酰肌醇锚定的。四个 Syndecans和至少五个Glypicans在哺乳动物中表达包括男人。细胞表面HSPG的生物学功能较差理解，但至少一个功能涉及调节细胞对多肽生长因子的反应。最近，一个人与组织失调相关的出生缺陷综合征是证明是由Glypican-3中无效突变引起的。遗传研究果蝇，果蝇，也将Glypican功能的损失与组织生长和图案的缺陷。一块glypicans 很可能发挥着特别重要的发展作用是紧张系统。培养的中性细胞和较低生物的实验具有长期以来指出HSPG在中性图案中的至关重要的作用指导和突触形成。该项目的先前工作已有证明Glypicans -1和-2是最丰富的HSPG之一在哺乳动物的大脑中，并在中性等位置表达前体区域，生长轴突和突触末端场，是与扮演这样的发展角色一致。目标的目标下一个项目时期的重点是揭示Glypicans-1和 -2在哺乳动物神经系统中，并关联Glypican功能具有Glypicans的结构特征，例如HS的存在链条，膜锚定模式以及大n-的存在终端球状域，不携带HS，但很高在整个进化中保守。功能实验涉及对缺乏Glypican-1，Glypican-2或两者的小鼠分析。 Glypican-2无效的老鼠已经制造了 Glypican-1无效小鼠正在进行中。结构功能分析 Glypicans的关系将使用果蝇作为实验编码变化的基因的基因可以迅速，并且定量测试功能。最后，观察结果突变表型和使结构/功能相关性将是用于指导与配体的遗传和生化搜索这些甘同性恋者在哺乳动物神经系统发育中相互作用。这些研究应提供有关重要和重要的洞察力理解的分子类别调节基本的发展过程，特别是在神经系统中。