Essential role of heparan sulfate 2-O-sulfotransferase in chick limb bud patterning and development
Essential role of heparan sulfate 2-O-sulfotransferase in chick limb bud patterning and development
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DOI：
10.1074/jbc.m610707200
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发表时间：
2007-07-06
影响因子：
4.8
通讯作者：
Kimata, Koji
中科院分区：
文献类型：
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作者：
Kobayashi, Takashi;Habuchi, Hiroko;Kimata, Koji
硫酸乙酰肝素（HS）与肝素结合生长因子（如成纤维细胞生长因子（FGF））的相互作用在很大程度上取决于链结构。在链上的各个位置的O-硫酸化是决定HS结构的主要因素;因此，O-硫酸化模式可能通过时空调节肝素结合生长因子的活性，在控制各种组织和器官的发育和形态发生过程中发挥至关重要的作用。在以前的研究中，我们发现，HS-2-O-磺基转移酶强烈表达在整个中胚层的鸡肢芽在发育的早期阶段。在这里，我们表明，抑制HS-2-O-磺基转移酶在未来的肢体地区的小抑制RNA导致截断肢芽和减少FGF-8的表达在顶端外胚层嵴。治疗还减少了间充质中的Fgf-10表达。此外，2-O-硫酸HS，通常丰富的基膜和中胚层下外胚层肢芽，显着减少处理芽。ERK和Akt的磷酸化水平在这种截短的芽中上调。因此，我们首次证明HS的2-O-硫酸化对于肢芽发育和生长所需的FGF信号传导至关重要。
The interactions of heparan sulfate (HS) with heparin-binding growth factors, such as fibroblast growth factors (FGFs), depend greatly on the chain structures. O-Sulfations at various positions on the chain are major factors determining HS structure; therefore, O-sulfation patterns may play a crucial role in controlling the developmental and morphogenetic processes of various tissues and organs by spatiotemporally regulating the activities of heparin-binding growth factors. In a previous study, we found that HS-2-O-sulfotransferase is strongly expressed throughout the mesoderm of chick limb buds during the early stages of development. Here we show that inhibition of HS-2-O-sulfotransferase in the prospective limb region by small inhibitory RNA resulted in the truncation of limb buds and reduced Fgf-8 expression in the apical ectodermal ridge. The treatment also reduced Fgf-10 expression in the mesenchyme. Moreover 2-O-sulfated HS, normally abundant in the basement membranes and mesoderm under ectoderm in limb buds, was significantly reduced in the treated buds. Phosphorylation levels of ERK and Akt were up-regulated in such truncated buds. Thus, we have shown for the first time that 2-O-sulfation of HS is essential for the FGF signaling required for limb bud development and outgrowth.