Colombres Marcela, Henríquez Juan Pablo, Reig Germán F, Scheu Jessica, Calderón Rosario, Alvarez Alejandra, Brandan Enrique, Inestrosa Nibaldo C
Centro de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Cell Physiol. 2008 Sep;216(3):805-15. doi: 10.1002/jcp.21465.
Wnt 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 Wnt 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-3beta (GSK-3beta) 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 Wnt signaling for neuronal morphogenesis.
Wnt因子是分泌型配体，可影响神经系统行为的不同方面，如神经发育、突触形成和神经退行性变。在不同的模型系统中，Wnt信号已被证明受硫酸乙酰肝素蛋白聚糖（HSPG）调控。目前尚不清楚HSPG在神经元行为背景下是否调节Wnt信号。在此我们证明，用内源性配体Wnt-7a激活Wnt信号会导致神经母细胞瘤N2a细胞系中神经突生长增加。有趣的是，肝素在N2a细胞和大鼠原代海马神经元培养物中均诱导糖原合酶激酶-3β（GSK-3β）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-连环蛋白稳定。在两种体外神经元模型中均发现几种细胞外基质和膜附着的HSPG表达。在N2a细胞分化时观察到特定HSPG表达的变化。综上所述，我们的研究结果表明，HSPG可能调节神经元形态发生的经典Wnt信号。
