Mechanisms of Axon-Schwann cell interactions

在脊椎动物的周围神经系统中，称为雪旺细胞的特殊胶质细胞形成髓鞘 鞘，其是快速动作电位传播以及神经元健康和存活所需的。的 髓磷脂在正常神经系统功能中的重要性可能最好由髓磷脂损失来强调， 在诸如脱髓鞘性周围神经病的疾病中观察到的轴突束的无效髓鞘再生。 髓鞘的这种破坏可导致永久性神经元损失、显著疼痛和发病率，并最终导致神经元损伤。 瘫痪目前，没有治疗方法可以预防脱髓鞘或增强髓鞘再生，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。 为了确定髓鞘形成胶质细胞发育的新调节因子，我们先前进行了大规模的正向表达。 斑马鱼的基因筛选通过筛选，我们在胞质分裂的奉献者（dock 1）中发现了新的突变体。 之前的研究表明，这些全局突变体在径向分选中表现出严重的缺陷， PNS在发育过程中的髓鞘形成。此外，我们的初步分析表明， dock 1在成年斑马鱼损伤后神经修复中的作用。Dock 1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Rho GTCRac 1。到目前为止，Dock 1功能没有作用 尽管Rac 1是已知的许旺细胞发育的调节因子，在这里， 我们建议使用斑马鱼和小鼠模型来剖析Dock 1控制PNS的机制 发展和修复。我们的目标是确定Dock 1在雪旺细胞中的功能（Aim 1）， Dock 1功能的上游和下游（目标2），并测试Dock 1是否是髓鞘维持或修复所必需的 在哺乳动物PNS中神经损伤后（目的3）。这些实验将共同定义 在发育、损伤和修复过程中，轴突-雪旺细胞相互作用的潜在机制， 为治疗人类神经病和周围神经损伤的新疗法奠定了基础。

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.