Spatio-temporal regulation of morphogenesis by heparan sulfate chains

硫酸乙酰肝素链对形态发生的时空调节

基本信息

批准号：
14082206
负责人：
KIMATA Koji
金额：
$ 114.56万
依托单位：
Aichi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

Heparan sulfate (HS) whose basic backbone structure consists of repeating disaccharide of glucuronosyl glucosamine has astronomical number of different structures by sulfation at different positions and by isomerization of glucuronosyl residue. HS usually locates on the cell surfaces and in the extracellular matrix and its structure alters in a spacio-temporal manner. Most of secretary and soluble cell growth factors, cytokines and morphogens which are well known to be required for important cell activities such as cell proliferation, cell differentiation and cell morphology, for example, FGF and Wnt, have properties to bind to HS. Therefore, we hypothesized that those factors, when they differ, may bind to the HS portions with different structures specifically so that each activity of those factors could be regulated by HS distinctively. In this study we first clarified that different factors actually bind to HS with different O-sulfation positions. We then subjected moue, chicken, Zebrafish, and Drosophila to the alteration of genes for HS O-sulfation enzymes, and observed apparent abnormality of organogenesis and tissue-morphogensis in those animals. We further provided some evidence to show that the observed abnormality was due to altered signalings of those factors which were caused, by the abnormal changes in HS structure. Taken together, our study revealed the occurrence of regulation mechanisms of the activities of cell growth factors and morphogens by HS chains.

硫酸乙酰肝素（HS）的基本主链结构由葡萄糖醛酸基葡萄糖胺的重复二糖组成，通过不同位置的硫酸化和葡萄糖醛酸基残基的异构化，具有天文数字的不同结构。 HS通常位于细胞表面和细胞外基质中，其结构以时空方式发生变化。已知大多数分泌性和可溶性细胞生长因子、细胞因子和形态发生素是重要细胞活动如细胞增殖、细胞分化和细胞形态所需的，例如FGF和Wnt，具有与HS结合的特性。因此，我们推测这些因子在不同时可能会特异性地与不同结构的HS部分结合，从而使这些因子的每种活性能够受到HS的独特调节。在这项研究中，我们首先阐明了不同的因子实际上与具有不同 O-硫酸化位置的 HS 结合。然后，我们对小鼠、鸡、斑马鱼和果蝇进行 HS O-硫酸化酶基因的改变，并观察到这些动物的器官发生和组织形态发生明显异常。我们进一步提供了一些证据来表明观察到的异常是由于 HS 结构的异常变化引起的那些因素的信号传导改变所致。综上所述，我们的研究揭示了 HS 链对细胞生长因子和形态发生素活性的调节机制。