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.
While it is well accepted that myelin is a biologically active membrane receiving and processing signals in bi-directional communication with the axons, the nature of the axonal signal, the receptors on oligodendrocyte or the intracellular signaling mechanisms that regulate myelin growth remain poorly understood in the CNS. This study will investigate whether FGF-FGF-Receptor signaling is a significant mechanism of axon-glial communication for the regulation of myelin growth and will elucidate the role of intracellular signaling molecules that are employed to transmit these signals within oligodendrocytes. 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.
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|Ishii, Akihiro; Furusho, Miki; Dupree, Jeffrey L et al. (2014) Role of ERK1/2 MAPK signaling in the maintenance of myelin and axonal integrity in the adult CNS. J Neurosci 34:16031-45|
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