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

描述（由申请人提供）：细胞外信号调节蛋白激酶1/2（ERK 1/2，经典MARK）细胞内信号转导级联被许多细胞外刺激激活，这些细胞外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ERK 1/2被认为是至关重要的一些过程中，其确切的功能作用尚未得到充分的分析。为了更好地阐明ERK 1/2信号转导在外周神经系统发育中的作用，我们利用Cre/loxp技术在发育的早期阶段特异性地在感觉神经元和雪旺细胞中条件性地表达ERK 1/2。ERK 1/2信号传导在雪旺细胞分化和髓鞘形成以及感觉神经元轴突生长中的精确体内功能将被定义。还将分析相关激酶ERK 5补偿ERK 1/2损失的能力。这些数据将进一步我们的理解由ERK 1/2在不同的细胞类型的调节的复杂功能，并澄清神经系统发育的重要营养因子所利用的细胞内途径。摘要声明：ERK 1/2信号传导的遗传性或偶发性破坏与颅面综合征、自闭症谱系障碍、神经性疼痛、神经纤维瘤病和各种癌症有关，但我们对该途径功能的理解仍然不完整。从这个建议的执行所产生的数据将是感兴趣的临床学科;探索ERK 1/2或ERK 5信号作为治疗靶点，寻求了解发育综合征的发病机制导致突变的调节ERK 1/2信号，或试图重新激活神经元或神经胶质细胞的程序，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.