Role of FGF-Signaling in Myelinogenesis

FGF 信号传导在髓鞘形成中的作用

• 批准号: 8531418
• 负责人: RASHMI BANSAL
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531418
• 关键词: Ablation; Address; Attenuated; Axon; Binding; Biology; Brain-Derived Neurotrophic Factor; CSPG4 gene; Caliber; Cells; Communication; Complex; Demyelinating Diseases; Development; Docking; Dose; Environment; FGF1 gene; FGF2 gene; FGFR2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptors; Genes; Genetic; Goals; Growth; Growth Factor; Growth Factor Receptors; Homeostasis; Human; In Vitro; Individual; Intervention; Knowledge; Ligands; Link; MAP Kinase Gene; MAPK3 gene; Maintenance; Membrane; Molecular; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Natural regeneration; Nature; Neural Conduction; Neuregulin 1; Neurons; Oligodendroglia; Peripheral Nervous System; Play; Proliferating; Proteins; Radial; Receptor Signaling; Recruitment Activity; Regulation; Role; Schwann Cells; Series; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Source; Staging; Testing; Thick; Transgenic Mice; computerized data processing; gain of function; in vivo; millisecond; myelination; neuronal growth; oligodendrocyte lineage; overexpression; postnatal; progenitor; public health relevance; remyelination; transcription factor

DESCRIPTION (provided by applicant): A key question in myelin biology is how oligodendrocytes (OLs) and Schwann cells are instructed to myelinate axons and what molecular mechanisms control myelin growth in order to allow efficient nerve conduction. While much progress has been made to define transcription factors that are essential for myelination, the signal transduction pathways that govern OL development, myelin growth and maintenance remain poorly understood. In the PNS, axonal neuregulin-1-typeIII has emerged as a 'master-regulator' of Schwann cell development and myelination. However, its role for myelinating CNS axons has been questioned. Our recent studies have revealed that FGFR1/2 (Fibroblast Growth Factor Receptor-1 & -2) signaling plays a significant role in the control of myelin growth in the CNS. We found that in mice lacking Fgfr1/2 (Fgfr1/2 KO), OL progenitors (OPCs) were able to proliferate, differentiate, and ensheath axons normally but were unable to fully upregulate major myelin genes and generate thick myelin sheaths in proportion to axon caliber (Furusho et al. J. Neurosci. 2012). Thus, these studies have uncovered a previously unrecognized function of FGFR1/2 signaling in OLs that contributes to the regulation of myelin sheath thickness and suggests that initial ensheathment of axons and subsequent myelin growth is likely to be distinctly regulated in the CNS. What intracellular signal transduction pathways are recruited downstream of the FGFRs in vivo during OL development, myelin growth and maintenance and the cellular source of the ligand are key questions that will be addressed here using both genetic loss-and gain-of-function approaches. In AIM I we will determine whether attenuated myelin growth in the Fgfr1/2 KO can be rescued by genetically elevating ERK1/2 activity in OLs, to test if the two are functionally linked in the in vivo context. We will also test the hypothesis that ERK1/2 and FGFR1/2 signaling is significant for OPC expansion at earliest stages of OPC maturation but becomes dispensable at later stages in the postnatal CNS. In Aim II, we will genetically uncouple binding of FGFRs with either FRS2 (FGF Receptor Substrate-2) or PLC?, immediate downstream targets of FGF-receptors, to parse their individual contributions in the regulation of myelinogenesis. In addition, we will completely ablate FRS2 in OL-lineage cells, to test the hypothesis that FRS2 serves as a key "intracellular control center" in OLs, integrating and amplifying signals from a subset of promyelinating growth factor receptors, primarily FGFRs and Trks. In Aim III we will over-express FGF1 or FGF2 postnatally in neurons of transgenic mice to test a potentially paradigm shifting hypothesis that FGF/FGFR interaction at the axon-glial interface is a significant mechanism for regulating axon-directed radial growth of the myelin sheath in the CNS. Overall, a better understanding of the signaling mechanisms that stimulate normal myelin sheath expansion are highly relevant to the ultimate goal of stimulating efficient remyelination in human demyelinating disorders, such as Multiple Sclerosis, where remyelination is often inefficient leading to myelin sheath that are thinner than normal.

描述（由申请人提供）：髓鞘生物学中的一个关键问题是少突胶质细胞（OL）和许旺细胞如何被指示使轴突髓鞘化，以及什么分子机制控制髓鞘生长以允许有效的神经传导。虽然已经取得了很大的进展，以确定转录因子是必不可少的髓鞘，信号转导途径，管理OL的发展，髓鞘的生长和维护仍然知之甚少。在PNS中，轴突neuregulin-1-typeIII已经成为雪旺细胞发育和髓鞘形成的“主调节因子”。然而，其作用的髓鞘中枢神经系统轴突一直受到质疑。我们最近的研究表明，FGFR 1/2（成纤维细胞生长因子受体-1和-2）信号在控制CNS中髓鞘生长中起着重要作用。我们发现，在缺乏Fgfr 1/2（Fgfr 1/2 KO）的小鼠中，OL祖细胞（OPC）能够正常增殖、分化和包裹轴突，但不能完全上调主要髓鞘基因并产生与轴突口径成比例的厚髓鞘（Furusho等人，J. Neurosci. 2012年）。因此，这些研究揭示了以前未被认识到的功能，FGFR 1/2信号在OL中，有助于髓鞘厚度的调节，并表明，轴突的初始鞘化和随后的髓鞘生长可能是明显的调节中枢神经系统。什么样的细胞内信号转导途径在OL发育、髓鞘生长和维持过程中在体内招募FGFR下游，以及配体的细胞来源是这里将使用遗传功能丧失和获得方法解决的关键问题。在AIM I中，我们将确定Fgfr 1/2 KO中的髓鞘生长减弱是否可以通过遗传提高OL中ERK 1/2活性来拯救，以测试两者在体内环境中是否功能性相关。我们还将检验假设 ERK 1/2和FGFR 1/2信号在OPC成熟的最早阶段对OPC扩增是重要的，但在出生后CNS的后期阶段变得不重要。在目的II中，我们将从遗传学上解偶联FGFR与FRS 2（FGF受体底物-2）或PLC？的结合，FGF受体的直接下游靶点，以解析它们在髓鞘生成调节中的单独贡献。此外，我们将完全消融OL谱系细胞中的FRS 2，以检验FRS 2作为OL中关键的“细胞内控制中心”的假设，整合和放大来自早髓鞘生长因子受体亚组的信号，主要是FGFR和Trks。在目的III中，我们将在转基因小鼠的神经元中过表达FGF 1或FGF 2，以测试一个潜在的范式转变假说，即在轴突-胶质细胞界面处的FGF/FGFR相互作用是调节髓鞘的轴突定向径向生长的重要机制 中枢神经系统的鞘。总的来说，更好地理解刺激正常髓鞘扩张的信号传导机制与刺激人类脱髓鞘疾病（例如多发性硬化症）中的有效髓鞘再生的最终目标高度相关，其中髓鞘再生通常效率低下，导致髓鞘比正常情况下更薄。