Myelinating Glia: Development, Function & Pathobiology
Séminaire FSER organisé par Jim Salzer (NYU School of Medicine) du 18 au 23 octobre 2010
Bruce Appel, Peter Brophy, Patrizia Casaccia, Gabriel Corfas, Bénédicte Dargent, Laura Feltri, Vittorio Gallo, Kristjan Jessen, Dies Meijer, Klaus-Armin Nave, Elior Peles, Brian Popko, Jim Salzer , William S. Talbot, Carla Taveggia, Terri Wood, Bernard Zalc.
A group of leading investigators met on October 18-23, 2010 to discuss emerging concepts in the biology and pathobiology of myelin and myelinated nerve fibers. Most of the data presented were unpublished and much of the discussion concerned the remaining, major unanswered questions in the field. Topics of discussion included: the roles of both myelinating and non-myelinating glial cells in axon biology, mechanisms of myelin sheath formation, regulation of the oligodendrocyte and Schwann cell lineage, formation of the domains of myelinated axons, demyelination and remyelination, and the role of myelinating glia in supporting axon function including whether myelin defects contribute to neuropsychiatric disorders.
The symposium began with a presentation by Bernard (Boris) Zalc (INSERM, Salpetriere Hospital, Paris) on the evolutionary origins of myelin which, based on the fossil record, is inferred to have arisen ~450 million years ago, coordinate with the acquisition in gnathostomes of a hinged-jaw. Related questions that recurred during the symposium include the heterogeneity of the oligodendrocyte (OLG) lineage, whether OLG function is independent of myelination, and whether electrical activity promotes myelination.
Several presentations focused on the mechanisms of myelin sheath formation. Data presented by Laura Feltri (San Raffaele, Milan) highlighted the sequential events required for peripheral nervous system (PNS) myelination, i.e. axon recognition and segregation and coordinated basal lamina deposition. Signaling pathways that mediate these events include Rho GTPases activated by integrins. Data from Elior (Ori) Peles (Weizmann Institute, Tel Aviv) further highlight the role of the actin-cytoskeleton and of N-WASP in the wrapping of the myelin sheath around axons by Schwann cells. Peter Brophy (Edinburgh) reviewed the molecular organization of the Cajal bands (sites where the outer Schwann cell membrane lies in close apposition to the myelin sheath). Mutant mice lacking Cajal bands do not show a consistent difference in internode length suggesting these structures have alternative roles than previously suspected.
Of related interest are the extrinsic and intrinsic signals that regulate myelination and demyelination. Teresa Wood (UMDNJ, Rutgers) described studies on OLGs where IGF growth factor signaling drives PI 3-kinase/Akt signaling and thereby mTOR signaling, which is required for myelination and effective remyelination. Current studies include identifying specific mTOR effectors and whether RICTOR and RAPTOR pathways have distinct roles in these events. Bruce Appel (U Colorado) described new mutant zebrafish that suggest signaling via retrogradely transported endosomes may be critical for myelination. Patrizia Casaccia (Mt. Sinai, New York) reviewed emerging evidence that epigenetic changes regulate both PNS and CNS myelination, in particular that histone acetylation is an important regulator of the transcription of specific, early genes including regulators of RNA processing, transcription, protein translation, and the cell cycle. Vittorio Gallo (Children’s Hospital, Washington DC) raised the key question of whether remyelination by oligodendrocyte precursors (OPCs) largely recapitulates development or not. His studies raise the possibility that electrical coupling (via AMPA currents) with callosal axons and endothelins secreted by astrocytes are key signals that promote OPC migration and differentiation.
Known sources of pro-myelinating signals for Schwann cells include neuregulin (NRG) 1 and ADAM22 on axons, and laminin in the basal lamina. Will Talbot (Stanford) presented evidence that type III NRG is not only important for Schwann cell survival but also regulates their directional migration. Work on NRG1 processing by Carla Taveggia (San Raffaele, Milan) indicates that the effects of the TACE secretase on NRG1 activity is opposite from that of BACE; these two secretases thereby have distinct effects on the extent of PNS myelination. Dies Meijer (Erasmus MC, Rotterdam) presented evidence that interactions of ADAM22 on axons with Lgi4 on Schwann cells is critical for PNS myelination; the signaling mechanisms currently remain obscure. Work from the Talbot lab also implicate Schwann cell GPR (G-coupled protein receptor) 126 in the commitment/onset phase of myelination via a cAMP-dependent mechanism; interestingly, in GPR126 deficient zebrafish, if Schwann cells transition beyond the promyelinating (1:1 relationship with axons) stage, later events of myelination are normal. Studies from the Feltri lab implicate laminin signaling via integrins and dystroglycan in promoting wrapping and myelination; these events depend on activation of several signaling pathways (Akt, GTPases, and FAK), to promote Schwann cell myelination. Promyelinating signals ultimately drive transcription factors in both Schwann cells and oligodendrocytes. Patrizia Casaccia (Mt. Sinai, New York) described studies in which the YY1 transcription factor was ablated in Schwann cells leading to an arrest of differentiation at the promyelinating stage. YY1 appears to be upstream of, and to regulate the expression of Krox-20, a key Schwann cell transcription factor. Dies Meijer also presented evidence that the Oct-6 enhancer element is regulated by SOX-10.
In addition to these promyelinating signals, several investigators described the reaction of myelinating glia to injury and the events associated with demyelination/remyelination. Kristjan Jessen (University College, London) is characterizing the activation of signaling pathways with injury, notably c-Jun. Conditional inactivation of c-Jun in Schwann cells results in impaired injury responses including slower myelin clearance, deficient axonal regeneration, and loss of neurons after injury. Brian Popko (U. Chicago) presented a genetic model of acute oligodendrocyte ablation in which a PLP Cre-ERT driver line was used to activate diptheria toxin in mature OLG. This is associated with OLG apoptosis, delayed but severe demyelination, followed by robust remyelination; he also reported there is a late phase of autoimmune-mediated demyelination in these animals after an additional period of several months.
Finally, the mechanisms by which myelinating glia maintain axon integrity and regulate axon function was discussed. Klaus Nave (Max Planck Institute, Gottingen) has shown that mice deficient in myelin proteins exhibit significant axon pathology even when the myelin sheaths appear morphologically normal. He discussed genetic models to investigate whether metabolic support is required to maintain the axon, and the possibility that inflammation directed against the OLGs may exacerbate axonal injury. Several speakers addressed the mechanisms by which glial cells direct the reorganization of axons into specific molecular domains. Benedicte Dargent (Université de la Méditerranée, Marseille) focused on how sodium channels accumulate at the axon initial segment (AIS), a site functionally and molecularly homologous to nodes of Ranvier. Studies using chimeric proteins indicate that sodium channel accumulation is driven by interactions with ankyrin G and are enhanced by casein kinase II phosphorylation. Ori Peles reviewed recent studies indicating that redundant mechanisms promote node of Ranvier assembly in the PNS, including signals driven by gliomedin at the node and by the flanking paranodal junctions. Jim Salzer (NYU, New York) presented studies that PNS nodes are assembled from distinct sources of proteins. Cell adhesion molecules redistribute to nascent nodes via diffusion trapping whereas intracellular stores of ion channels are transported to this site. In older animals, after paranode formation, all components are transported to the node. Peter Brophy demonstrated that NF186 is essential for node formation but not its maintenance. In contrast, the integrity of the AIS is dependent on ongoing expression of NF186 strongly suggesting that the AIS is subject to ongoing plasticity/remodeling. Mice without an AIS appear surprisingly normal; preliminary electrophysiological data suggest that the first node assumes the role of the AIS in initiating the axon potential. Finally, Gabriel Corfas (Children’s Hospital, Boston) described neurobehavioral disorders in a dominant-negative transgenic construct that inhibits EGF/neuregulin signaling in OLGs. These data also implicate dopaminergic signaling as being regulated unexpectedly by OLGs, suggesting a possible link of myelin to schizophrenia and other psychiatric conditions.
The intimate, beautiful conference setting and a meeting format which enabled extensive, informal interactions, elicited spirited discussions among the participants on a variety of topics, scientific and otherwise. The meeting created a collegial and collaborative esprit among the attendees remarkable for a scientific gathering – discussions, story telling, and impromptu piano performances continued well after the day’s formal sessions were over. By general consensus, this meeting was a uniquely stimulating and enriching experience that will be remembered by all of the participants as the best conference they have ever attended.