Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality
Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality
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DOI：
10.1074/jbc.m607434200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Kimata, Koji
中科院分区：
文献类型：
--
作者：
Habuchi, Hiroko;Nagai, Naoko;Kimata, Koji
硫酸乙酰肝素（HS）能够以结构依赖的方式与参与细胞信号传导的许多生长因子相互作用，在多种发育、生理和致病过程中发挥关键作用。HS糖胺聚糖的不同结构是几种N-和o -磺基转移酶、c5 - epimase和6- o -磺基内酯酶协同作用的结果。我们已经证明，HS中氨基葡萄糖残基的6- o硫酸化是由硫转移酶HS6ST-1、-2和-3催化的。为了确定HS6ST-1的生物学和生理学重要性，我们现在描述了缺乏这种硫转移酶的转基因小鼠的创建。大多数hs6st -1缺失小鼠在胚胎15.5天和围产期之间死亡，存活的小鼠比野生型小鼠要小得多。其中一些hs6st -1缺失小鼠表现出发育异常，对这些小鼠的组织化学和分子分析显示，与野生型小鼠相比，胎盘迷路区胎儿微血管的数量减少了50%。由于我们观察到hs6st -1缺失小鼠组织中VEGF-A mRNA和蛋白的适度减少，细胞因子信号中hs依赖性缺陷可能导致胚胎死亡率增加和生长减慢。从我们的hs6st -1缺失小鼠的各个器官中分离的HS链的生化研究表明，GlcNAc（6SO(4)）和HexA-GlcNSO(3)（6SO(4)）水平显著降低，结合Wnt2的能力降低。因此，尽管小鼠基因组中存在三个密切相关的6- o -硫转移酶基因，但在大多数组织中，HS6ST-1是用于HS生物合成的主要基因。
Heparan sulfate (HS) plays critical roles in a variety of developmental, physiological, and pathogenic processes due to its ability to interact in a structure-dependent manner with numerous growth factors that participate in cellular signaling. The divergent structures of HS glycosaminoglycans are the result of the coordinate actions of several N- and O-sulfotransferases, C5-epimerase, and 6-O-endosulfatases. We have shown that 6-O-sulfation of the glucosamine residues in HS are catalyzed by the sulfotransferases HS6ST-1, -2, and -3. To determine the biological and physiological importance of HS6ST-1, we now describe the creation of transgenic mice that lack this sulfotransferase. Most of our HS6ST-1-null mice died between embryonic day 15.5 and the perinatal stage, and those mice that survived were considerably smaller than their wild-type littermates. Some of these HS6ST-1-null mice exhibited development abnormalities, and histochemical and molecular analyses of these mice revealed an similar to 50% reduction in the number of fetal microvessels in the labyrinthine zone of the placenta relative to that in the wild-type mice. Because we observed a modest reduction in VEGF-A mRNA and protein in the tissues of HS6ST-1-null mice, an HS-dependent defect in cytokine signaling probably contributes to increased embryonic lethality and decreased growth. Biochemical studies of the HS chains isolated from various organs of our HS6ST-1-null mice revealed a marked reduction of GlcNAc(6SO(4)) and HexA-GlcNSO(3)(6SO(4)) levels and a reduced ability to bind Wnt2. Thus, despite the presence of three closely related 6-O-sulfotransferase genes in the mouse genome, HS6ST-1 is the primary one used in HS biosynthesis in most tissues.