Mechanisms of Axon-Schwann cell interactions

在脊椎动物的周围神经系统(PNS)中，被称为雪旺细胞的特殊神经胶质细胞形成髓鞘 鞘，这是快速的动作电位传播以及神经元健康和生存所必需的。这个 髓鞘在正常神经系统功能中的重要性，也许最好的突显是髓鞘丢失和 在脱髓鞘周围神经病等疾病中观察到的轴突束无效率的再髓鞘形成。 这种髓鞘的破坏可能导致永久性神经元丢失、严重的疼痛和疾病，并最终 瘫痪。目前，尚无预防脱髓鞘或增强再髓鞘形成的治疗方法，部分原因是 我们对髓鞘形成的遗传和分子控制的不完全理解。 为了确定髓鞘胶质细胞发育的新调节因素，我们以前进行了一项大规模的前瞻 斑马鱼的基因筛查。通过这一筛选，我们发现了胞质分裂奉献因子(DOCK1)的新突变体 而此前的研究表明，这些全局突变体在径向排序和还原方面表现出严重的缺陷 三叉神经节发育过程中的髓鞘形成。此外，我们的初步分析表明， DOCK1在成年斑马鱼损伤后神经修复中的作用DOCK1编码高度保守的非典型鸟嘌呤 核苷酸交换因子可以激活小的Rho GTP酶rac1。到目前为止，DOCK1功能没有角色 尽管rac1是已知的雪旺细胞发育的调节因子，但它在雪旺细胞中的作用已被描述。这里, 我们建议使用斑马鱼和小鼠模型来剖析DOCK1控制PNS的机制 开发和修复。我们的目标是确定DOCK1在雪旺细胞中的功能(目标1)，揭示信号转导途径 DOCK1功能的上下游(目标2)，并测试是否需要DOCK1来维持或修复髓鞘 哺乳动物三叉神经节神经损伤后(目标3)。总之，这些实验将定义基本的 轴突-雪旺细胞相互作用在发育、损伤和修复中的潜在机制 为治疗人类神经病和周围神经损伤的新疗法奠定基础。

In the vertebrate peripheral nervous system (PNS), specialized glial cells called Schwann cells form the myelin sheath, which is required for fast action potential propagation as well as neuronal health and survival. The importance of myelin in normal nervous system function is perhaps best underscored by myelin loss and inefficient remyelination of axon tracts observed in diseases such as demyelinating peripheral neuropathies. Such disruptions of myelin can lead to permanent neuron loss, significant pain and morbidity, and ultimately paralysis. Currently, no treatments exist to prevent demyelination or to enhance remyelination, in part because of our incomplete understanding of the genetic and molecular control of myelination. To identify new regulators of myelinating glial cell development, we previously performed a large-scale forward genetic screen in zebrafish. Through this screen, we identified new mutants in dedicator of cytokinesis (dock1) and previously showed that these global mutants exhibit severe defects in radial sorting and reduced myelination in the PNS during development. Moreover, our preliminary analyses suggest a critical function for Dock1 in nerve repair following injury in adult zebrafish. Dock1 encodes a highly conserved atypical guanine nucleotide exchange factor that can activate the small Rho GTPase Rac1. To date, no role for Dock1 function in Schwann cells has been described, although Rac1 is a known regulator of Schwann cell development. Here, we propose to use zebrafish and mouse models to dissect the mechanisms by which Dock1 controls PNS development and repair. We aim to define the function of Dock1 in Schwann cells (Aim 1), uncover pathways up- and downstream of Dock1 function (Aim 2), and test if Dock1 is required for myelin maintenance or repair following nerve injury in the mammalian PNS (Aim 3). Together, these experiments will define fundamental mechanisms underlying axon-Schwann cell interactions in development, injury, and repair and can lay the foundation for new therapies to treat human neuropathies and peripheral nerve damage.