Spatio-temporal regulation of morphogenesis by heparan sulfate chains

硫酸乙酰肝素（HS）的基本骨架结构由葡萄糖醛酸氨基葡萄糖的重复二糖组成，通过在不同位置的硫酸化和葡萄糖醛酸残基的异构化，可以产生大量不同的结构。HS通常位于细胞表面和细胞外基质中，其结构具有时空变化性。众所周知，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（morphogens）是重要细胞活性（如细胞增殖、细胞分化和细胞形态）所必需的，例如FGF和Wnt，具有与HS结合的性质。因此，我们推测，这些因子，当他们不同，可能会结合到HS部分具有不同的结构特异性，使这些因子的每一个活动可以由HS独特的调节。在这项研究中，我们首先澄清，不同的因素实际上结合到HS不同的O-硫酸化位置。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，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，所观察到的异常是由于改变了这些因素的信号，引起的HS结构的异常变化。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。

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.