Heparin activates Wnt signaling for neuronal morphogenesis
Heparin activates Wnt signaling for neuronal morphogenesis
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DOI：
10.1002/jcp.21465
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发表时间：
2008-09-01
影响因子：
5.6
通讯作者：
Inestrosa, Nibaldo C.
中科院分区：
文献类型：
--
作者：
Colombres, Marcela;Henriquez, Juan Pablo;Inestrosa, Nibaldo C.
Writ因子是影响神经系统行为的不同方面如神经发育、突触发生和神经变性的分泌配体。在不同的模型系统中，Wnt信号转导已被证明是由硫酸乙酰肝素蛋白聚糖（HSPG）调节。HSPGs是否在神经元行为的背景下调节Writ信号传导目前尚不清楚。在这里，我们证明了Wnt信号与内源性配体Wnt-7a的激活导致神经母细胞瘤N2 a细胞系中神经突生长的增加。有趣的是，在N2 a细胞和大鼠原代海马神经元培养物中，肝素诱导糖原合成酶激酶-3 β（GSK-3 β）抑制、β-连环蛋白稳定和形态分化。我们还表明，肝素调节Wnt-3a诱导的β-连环蛋白的稳定。几种细胞外基质和膜附着的HSPGs被发现在两种体外神经元模型中表达。在N2 a细胞分化后观察到特异性HSPGs表达的变化。两者合计，我们的研究结果表明，HSPGs可能会调节典型的Writ信号神经元形态发生。
Writ factors are secreted ligands that affect different aspects of the nervous system behavior like neurodevelopment, synaptogenesis and neurodegeneration. In different model systems, Wnt signaling has been demonstrated to be regulated by heparan sulfate proteoglycans (HSPGs). Whether HSPGs modulate Writ signaling in the context of neuronal behavior is currently unknown. Here we demonstrate that activation of Wnt signaling with the endogenous ligand Wnt-7a results in an increased of neurite outgrowth in the neuroblastoma N2a cell line. Interestingly, heparin induces glycogen synthase kinase-3 beta (GSK-3 beta) inhibition, beta-catenin stabilization and morphological differentiation in both N2a cells and in rat primary hippocampal neuronal cultures. We also show that heparin modulates Wnt-3a-induced stabilization of beta-catenin. Several extracellular matrix and membrane-attached HSPGs were found to be expressed in both in vitro neuronal models. Changes in the expression of specific HSPGs were observed upon differentiation of N2a cells. Taken together, our findings suggest that HSPGs may modulate canonical Writ signaling for neuronal morphogenesis.