Role of ERK1/ERK2 MAP Kinase in Myelin Assembly and Maintenance

描述(申请人提供)：由少突胶质细胞(OL)包裹轴突周围的髓鞘对于所需的电信号的快速传导至关重要 中枢神经系统的正常运作。髓鞘形成是一个多步骤的过程，包括OL祖细胞(OPC)的增殖，适时分化为OL，轴突被套，最后髓鞘在髓鞘形成高峰期迅速扩张，然后在成年期逐渐生长。虽然已经确定了OL发育早期的许多调节因子，但在我们对特定的细胞内信号事件的理解中存在着显著的差距 整合在控制髓鞘形成后期的OL中，使其厚度与轴突口径成比例增加。了解这一机制具有临床意义，因为目前尚不清楚为什么多发性硬化症在重新髓鞘形成过程中形成的髓鞘无法达到正常厚度。这一建议主要解决了髓鞘组装和维持在中枢神经系统中如何调控的重要问题，假设ERK1/2-MAPK(细胞外信号调节激酶-1/2)是多种外部信号的重要中介，在这些过程中发挥核心作用。这是基于我们最近的发现，缺乏ERK1/2的OL特异性表达的小鼠无法上调主要髓鞘基因的转录，并且无法产生厚厚的髓鞘。这与OPC的轴突增殖、分化和包膜无关，因为这些事件在ERK1/2基因敲除小鼠中仍然不受影响。这些结果代表了一个重要的概念范式转变，因为它们表明，与PNS相反，OL分化/起始和随后髓鞘厚度的增加受到明显调控，在PNS中，一个信号同时控制OL分化和髓鞘形成。为了进一步了解ERK1/2在复杂的活体环境中的作用，我们试图使用一系列具有ERK1/2功能遗传缺失或获得的转基因小鼠模型来解决以下具体问题。在目标I中，在成熟的OL中，ERK1/2的消融将在发育后期和成年期被诱导，我们将研究ERK1/2在成年期髓鞘生长和维持的长期进展中的作用。在AIM II中，使用在发育过程中OPC和OL或成年期成熟OL中ERK1/2活性升高的小鼠，我们将阐明ERK1/2在OL发育和髓鞘形成中的作用。总体而言，本文提出的最先进的遗传丧失和功能获得相结合的方法有望增强我们对ERK1/2信号在OL分化和活跃的髓鞘生物形成过程中的功能意义的理解，以及在成年后维持其逐渐增长和维持，并将这一知识应用于对诸如MS等脱髓鞘疾病的知情干预治疗。

DESCRIPTION (provided by applicant): Wrapping of the myelin sheath around axons by oligodendrocytes (OLs) is critical for the rapid conduction of electrical signals that are required for normal functioning of the CNS. Myelination is a multistep process involving the proliferation of OL progenitors (OPCs), timely differentiation into OLs, ensheathment of axons and finally rapid expansion of myelin sheath during the peak of myelination followed by gradual growth in adulthood. While many regulators of the early stages of OL development have been identified, there are significant gaps in our understanding of the specific intracellular signaling events that are integrated within the OLs that control later phases of myelinogenesis to increase its thickness in proportion to axon caliber. Understanding this mechanism is clinically relevant since it is unclear why the myelin that is formed during remyelination in Multiple Sclerosis fails to achieve normal thickness. This proposal primarily addresses the important question of how myelin assembly and maintenance are regulated in the CNS, hypothesizing that ERK1/2-MAPK (Extracelluar Signal Regulated Kinases-1/2), important mediators of multiple external signals, plays a central role in these processes. This is based on our recent findings that mice lacking OL-specific expression of ERK1/2 fail to up- regulate the transcription of major myelin genes and are unable to generate thick myelin sheaths. This is independent of OPC proliferation, differentiation and ensheathment of axons since these events remain unaffected in the Erk1/2 knockout mice. These results represent an important conceptual paradigm shift as they suggest that OL differentiation/initiation and subsequent increase in myelin thickness are distinctly regulated, in contrast to the PNS, where one signal controls both OL differentiation and myelination. To obtain further insights into the role of ERK1/2 in the complex in vivo environment, we seek to address the following specific questions using a series of transgenic mice models with genetic loss or gain of ERK1/2 function. In Aim I, using mice where ablation of Erk1/2 in mature OLs will be induced at a later point in development and in adulthood, we will examine the role of ERK1/2 on the long- term progression of myelin growth and maintenance in adulthood. In Aim II, using mice where ERK1/2 activity will be elevated in OPCs and OLs during development or in mature OLs during adulthood, we will elucidate the role of ERK1/2 in OL development and myelin assembly during active myelination and in adulthood. Overall, a combination of state-of-the-art genetic loss- and gain-of-function approaches as proposed here are expected to enhance our understanding of the functional significance of ERK1/2 signaling both during OL differentiation and active myelin biogenesis, as well as to sustain its gradual growth and maintenance in adulthood, and to apply this knowledge for an informed intervention in the treatment of demyelinating diseases such as MS.