Spatio-temporal regulation of morphogenesis by heparan sulfate chains

硫酸乙酰肝素(HS)的基本骨架结构是由葡萄糖醛酸氨基葡萄糖的重复二糖组成，通过不同位置的硫酸盐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，其结构以时空方式改变。大多数已知在细胞增殖、细胞分化和细胞形态等重要细胞活动中所必需的分泌型和可溶性细胞生长因子、细胞因子和形态因子，如成纤维细胞生长因子和Wnt，都具有与HS结合的特性。因此，我们假设，当这些因子不同时，它们可能特定地结合到具有不同结构的HS部分，从而这些因子的每一种活性都可以被HS区别地调节。在这项研究中，我们首先阐明了不同的因素实际上与具有不同O-硫化位置的HS结合。然后，我们对老鼠、鸡、斑马鱼和果蝇进行了HS O-硫酸盐化酶基因的改变，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子的信号改变所致。综上所述，我们的研究揭示了HS链对细胞生长因子和形态因子活性的调控机制。

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.