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Abstract：
Correct axonal growth during nervous system development is critical for synaptic transduction and nervous system function. Proper axon outgrowth relies on a suitable growing environment and the expression of a series of endogenous neuronal factors. However, the mechanisms of these neuronal proteins involved in neuronal development remain unknown. ZDHHC17 is a member of the DHHC (Asp-His-His-Cys)-containing family, a family of highly homologous proteins. Here, we show that loss of function of ZDHHC17 in zebrafish leads to motor dysfunction in 3-day post-fertilization (dpf) larvae. We performed immunolabeling analysis to reveal that mobility dysfunction was due to a significant defect in the axonal outgrowth of spinal motor neurons (SMNs) without affecting neuron generation. In addition, we found a similar phenotype in zdhhc17 siRNA-treated neural stem cells (NSCs) and PC12 cells. Inhibition of zdhhc17 limited neurite outgrowth and branching in both NSCs and PC12. Furthermore, we discovered that the level of phosphorylation of extracellular-regulated kinase (ERK) 1/2, a major downstream effector of tyrosine kinase (TrkA), was largely upregulated in ZDHHC17 overexpressing PC12 cells by a mechanism independent on its palmitoyltransferase (PAT) activity. Specifically, ZDHHC17 is necessary for proper TrkA-tubulin module formation in PC12 cells. These results strongly indicate that ZDHHC17 is essential for correct axon outgrowth in vivo and in vitro. Our findings identify ZDHHC17 as an important upstream factor of ERK1/2 to regulate the interaction between TrkA and tubulin during neuronal development.
摘要：
神经系统发育过程中正确的轴突生长对于突触转导和神经系统功能至关重要。适当的轴突生长依赖于合适的生长环境和一系列内源性神经元因子的表达。然而,这些神经元蛋白参与神经元发育的机制仍然未知。ZDHHC17是DHHC（Asp-His-His-Cys）家族的成员，一个高度同源的蛋白质家族。这里,我们表明，斑马鱼中ZDHHC17功能的丧失会导致受精后3天（dpf）幼虫的运动功能障碍。我们进行了免疫标记分析，以揭示移动性功能障碍是由于脊髓运动神经元（SMN）轴突生长的显着缺陷而不影响神经元的生成。此外,我们在zdhhc17siRNA处理的神经干细胞(NSCs)和PC12细胞中发现了相似的表型.zdhhc17的抑制限制了神经突生长和NSC和PC12中的分支。此外，我们发现，细胞外调节激酶（ERK）1/2的磷酸化水平，酪氨酸激酶（TrkA）的主要下游效应，在ZDHHC17过表达的PC12细胞中，其表达水平是通过一种独立于其棕榈酰转移酶（PAT）活性的机制而上调的。具体来说,ZDHHC17对于PC12细胞中适当的TrkA-微管蛋白模块形成是必需的。这些结果强烈表明ZDHHC17对于体内和体外正确的轴突生长是必需的。我们的发现将ZDHHC17确定为ERK1/2的重要上游因子，以调节神经元发育过程中TrkA与微管蛋白之间的相互作用。
