Role of FGF-Signaling in Myelinogenesis

髓磷脂生物学的一个关键问题是少突胶质细胞（OLs）和雪旺细胞是如何被指示形成髓鞘轴突的，以及什么分子机制控制髓磷脂的生长以实现有效的神经传导。虽然在确定髓鞘形成所必需的转录因子方面取得了很大进展，但对控制OL发育、髓鞘生长和维持的信号转导途径仍知之甚少。在PNS中，轴突神经调节蛋白1- iii型已成为雪旺细胞发育和髓鞘形成的“主调节因子”。然而，其在中枢神经系统轴突髓鞘形成中的作用一直受到质疑。我们最近的研究表明，FGFR1/2（成纤维细胞生长因子受体1 & 2）信号在中枢神经系统髓磷脂生长的控制中起着重要作用。我们发现，在缺乏Fgfr1/2 （Fgfr1/2 KO）的小鼠中，OL祖细胞（OPCs）能够正常增殖、分化和鞘轴突，但不能完全上调主要髓磷脂基因并产生与轴突直径成比例的厚髓鞘（Furusho等）。神经科学，2012)。因此，这些研究揭示了FGFR1/2信号在OLs中一个以前未被认识到的功能，该功能有助于髓鞘厚度的调节，并表明轴突的初始嵌套和随后的髓鞘生长可能在中枢神经系统中受到明显调节。在OL发育、髓鞘生长和维持以及配体的细胞来源过程中，FGFRs下游的细胞内信号转导途径是什么，这些是本文将使用遗传损失和功能获得方法来解决的关键问题。在AIM I中，我们将确定Fgfr1/2 KO中减弱的髓鞘生长是否可以通过在OLs中遗传提高ERK1/2活性来挽救，以测试两者在体内是否具有功能联系。我们也将检验这个假设

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.