Regulation of axon growth and regeneration by the DLK signaling pathway

在多细胞生物中，细胞之间通过一系列信号分子相互沟通，以控制其生长、分化和代谢。这些分子携带的信息在细胞表面被接收，并通过信号通路网络在细胞内传递，最终调节基因表达。这些通路功能的改变可导致一系列缺陷，从发育异常到许多疾病，包括癌症、糖尿病和神经退行性疾病。在NSERC的支持下，我们研究了一种名为双亮氨酸拉链激酶（dual leucine zipper kinase， DLK）的蛋白激酶的作用和特异性，DLK是参与多种生物功能的信号通路的上游组分。有趣的是，最近在不同模式生物中进行的遗传研究强调了DLK在轴突生长中的作用，轴突生长是神经系统发育和修复的关键过程。然而，DLK究竟如何介导轴突形成是一个重要的问题，仍然没有完全回答。通过对培养神经元的转录组分析，我们的实验室最近证明DLK控制着一些与神经元投射和分化相关的基因的表达。由于这些结果提供了DLK促进轴突生长的机制的指示，我们建议通过检查这些基因如何被DLK调节以及它们如何介导DLK在神经元中的作用来继续我们的研究。预计这些研究将大大扩展我们对DLK对轴突生长的作用的认识，并为再生医学和神经组织工程提供具有重要价值的信息。

Cells in multicellular organisms communicate with each other through a number of signaling molecules in order to control their growth, differentiation and metabolism. Information carried by these molecules is received at the cell surface and transmitted intracellularly by networks of signaling pathways that ultimately modulate gene expression. Alterations in the function of these pathways can lead to a spectrum of defects ranging from developmental abnormalities to numerous diseases, including cancer, diabetes and neurodegenerative disorders. With support from NSERC, we investigate the role and specific properties of a protein kinase named dual leucine zipper kinase (DLK), the upstream component of a signaling pathway involved in multiple biological functions. Interestingly, recent genetic studies carried out in different model organisms have highlighted a role for DLK in axon growth, a process crucial for development and repair of the nervous system. However, exactly how DLK mediates axon formation is an important question still not fully answered. Through transcriptome analysis of cultured neurons, our laboratory has recently demonstrated that DLK controls the expression of a number of genes associated with neuron projection and differentiation. Because such results provide an indication of the mechanism by which DLK contributes to axon growth, we propose to pursue our investigation by examining how these genes are regulated by DLK and how they might mediate the effects of DLK in neurons. It is anticipated that these studies will greatly expand our understanding of DLK's action on axon growth and generate information of great value for regenerative medicine and neural tissue engineering.