The In Vivo Role of ERK1/2 Signaling in Peripheral Nervous System Development

描述(申请人提供)：细胞外信号调节蛋白激酶1/2(ERK1/2，经典的Mark)细胞内信号转导级联被许多细胞外刺激激活，这些刺激在神经系统发育、可塑性和再生的各个方面发挥重要作用。虽然ERK1/2被认为在许多过程中是至关重要的，但其确切的功能作用尚未得到充分的分析。为了更好地阐明ERK1/2信号在周围神经系统发育中的作用，我们利用Cre/loxP技术有条件地灭活了发育早期的感觉神经元和雪旺细胞中的ERK1/2。ERK1/2信号在雪旺细胞分化、髓鞘形成和感觉神经元轴突生长中的确切作用将被定义。相关的激酶ERK5补偿ERK1/2丢失的能力也将被分析。这些数据将进一步加深我们对ERK1/2在不同细胞类型中调节的复杂功能的理解，并阐明一种对神经系统发育至关重要的营养因子所利用的细胞内途径。摘要：ERK1/2信号通路的遗传或零星中断与颅面综合征、自闭症谱系障碍、神经病理性疼痛、神经纤维瘤病和各种癌症有关，但我们对这一通路的功能了解仍不完全。这项建议的执行所产生的数据将对临床学科产生兴趣；探索ERK1/2或ERK5信号作为治疗目标，试图了解由ERK1/2信号调节因子突变导致的发育综合征的发病机制，或试图重新激活神经元或神经胶质程序以诱导或修改神经系统再生。

DESCRIPTION (provided by applicant): The Extracellular signal-Regulated protein Kinase1/2 (ERK1/2, classical MARK) intracellular signal transduction cascade is activated by numerous extracellular stimuli that play important roles in various aspects of nervous system development, plasticity, and regeneration. Although ERK1/2 is thought to be vital for a number of processes its precise functional role has not been adequately analyzed. To better clarify the role of ERK1/2 signaling in peripheral nervous system development, we have utilized Cre/loxp technology to conditionally inactivate ERK1/2 specifically in sensory neurons and Schwann cells at early stages of development. The precise in vivo function of ERK1/2 signaling in Schwann cell differentiation and myelination and sensory neuron axon growth will be defined. The ability of the related kinase, ERK5, to compensate for loss of ERK1/2 will also be analyzed. These data will further our understanding of the complex functions regulated by ERK1/2 in separate cell types and clarify the intracellular pathways utilized by a trophic factors important for nervous system development. Summary Statement: Genetic or sporadic disruption of ERK1/2 signaling has been implicated in craniofacial syndromes, autism spectrum disorders, neuropathic pain, neurofibramatosis, and various cancers, yet our understanding of the functions of this pathway remain incomplete. The data arising from the execution of this proposal will be of interest to clinical disciplines; exploring ERK1/2 or ERK5 signaling as a therapeutic target, seeking to understand the pathogenesis of developmental syndromes resulting from mutations in regulators of ERK1/2 signaling, or attempting to reactivate neuronal or glial programs to induce or modify nervous system regeneration.