Heparin-binding growth factor, pleiotrophin, mediates neuritogenic activity of embryonic pig brain-derived chondroitin sulfate/dermatan sulfate hybrid chains
Heparin-binding growth factor, pleiotrophin, mediates neuritogenic activity of embryonic pig brain-derived chondroitin sulfate/dermatan sulfate hybrid chains
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DOI：
10.1074/jbc.m413423200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Sugahara, K
中科院分区：
文献类型：
--
作者：
Bao, XF;Mikami, T;Sugahara, K
硫酸软骨素（CS）和硫酸皮肤素（DS）链在中枢神经系统中发挥作用。最值得注意的是，CS/ DS杂交链（E-CS/ DS）纯化胚胎猪脑结合生长因子和促进神经突生长向胚胎小鼠海马神经元的文化。然而，神经突发生的机制还不清楚。在这里，我们表明，多效生长因子（PTN），肝素结合生长因子，主要由神经胶质细胞产生，是主要的结合伙伴E-CS/DS在新生大鼠脑的膜相关蛋白组分。在PTN柱上将CS/ DS链分离为未结合、低亲和力和高亲和力级分。后两个馏分分别促进树突和轴突样神经突的生长，而未结合的馏分没有表现出这样的活动。通过抗PTN抗体或当从培养物中去除神经胶质细胞时，低亲和力级分的活性被消除。相比之下，高亲和力级分在这两种条件下都显示出活性。因此，主要来自胶质细胞的PTN介导低亲和力组分的活性，而不是高亲和力组分的活性。抗CS抗体473 HD中和了两种组分的神经突发生活性。相互作用分析表明E-CS/DS链上的473 HD表位和PTN结合结构域在很大程度上重叠。这三个亲和亚组分的二糖组成和（L）-艾杜糖醛酸的分布沿沿着链。多硫酸化的二糖和非连续的含艾杜糖醛酸的单元是E-CS/DS链结合PTN并表现出神经元生成活性的必要条件。因此，在哺乳动物脑中具有不同结构的CS亚群通过不同的分子机制在轴突发生中发挥不同的作用，至少部分通过调节生长因子的功能。
Chondroitin sulfate ( CS) and dermatan sulfate (DS) chains play roles in the central nervous system. Most notably, CS/ DS hybrid chains (E-CS/ DS) purified from embryonic pig brains bind growth factors and promote neurite outgrowth toward embryonic mouse hippocampal neurons in culture. However, the neuritogenic mechanism is not well understood. Here we showed that pleiotrophin ( PTN), a heparin-binding growth factor, produced mainly by glia cells, was the predominant binding partner for E-CS/DS in the membrane-associated protein fraction of neonatal rat brain. The CS/ DS chains were separated on a PTN column into unbound, low affinity, and high affinity fractions. The latter two fractions promoted outgrowth of dendrite- and axonlike neurites, respectively, whereas the unbound fraction showed no such activity. The activity of the low affinity fraction was abolished by an anti-PTN antibody or when glia cells were removed from the culture. In contrast, the high affinity fraction displayed activity under both these conditions. Hence, PTN mainly from glia cells mediated the activity of the low affinity but not the high affinity fraction. The anti-CS antibody 473HD neutralized the neuritogenic activities of both fractions. Interaction analysis indicated that the 473HD epitope and PTN-binding domains in the E-CS/DS chains largely overlap. The three affinity subfractions differed in disaccharide composition and the distribution of (L)-iduronic acid-containing disaccharides along the chains. Oversulfated disaccharides and nonconsecutive iduronic acid-containing units were the requirements for the E-CS/DS chains to bind PTN and to exhibit the neuritogenic activities. Thus, CS subpopulations with distinct structures in the mammalian brain play different roles in neuritogenesis through distinct molecular mechanisms, at least in part by regulating the functions of growth factors.