TOP ＞ Symposia

Symposia Current topics of myelin biology and beyond／ミエリンバイオロジーの進歩 2S2-1 Recent advances in myelin biology Kazuhiro Ikenaka Division of Neurobiology and Bioinfomatics, National Institute for Physiological Sciences The white matter is a region through which axons project to their targets to make neural circuits. Long projection axons are usually covered with myelin, which is rich in lipids, thus making the white matter appear white. Myelin increases the conduction velocity by inducing saltatory conduction. During myelin formation it is well known that extensive neuro-glial (axon-myelin) interaction takes place; for example, induction of terminal differentiation of oligodendrocytes by axonal electric activity, and ion channel clustering on the axonal surface and axonal diameter increase caused by myelin membrane. Recently, this neuro-glial interaction has been demonstrated to be continuing even after completion of myelin formation: elevation of calcium levels in myelin/oligodendrocyte is evoked by axonal activity, and increase in the conduction velocity by hyper-polarization of oligodendrocyte (Yamazaki et al., 2007). These new findings suggested more complex function of myelin, especially toward higher brain function. Indeed, evidences are accumulating to support that myelin is involved in learning and cognition. In this symposium we will discuss the significance of the myelin in higher brain functions and its disorder. 2S2-2 A novel Olig2-binding factor is indispensable for oligodendrocyte development in central nervous system Hirohide Takebayashi，Norihisa Bizen Div Neuroanat. Grad Sch Med & Dent Sci, Niigata Univ Oligodendrocytes form the myelin sheaths around axons and regulate the axonal conduction in central nervous system. The failure of oligodendrocyte development leads to the misregulation of neuronal networks and thereby intractable neuronal disorders. Although Olig2 transcription factor is essential for motoneuron and oligodendrocyte development, it remains unclear how Olig2 predominates in oligodendrocyte development. To elucidate the molecular basis underlying Olig2-mediated oligodendrocyte development, we have sought Olig2-binding molecules, which cooperate with Olig2 for oligodendrogenesis. Yeast two hybrid screening using cDNA libraries prepared from mouse embryonic brains identified several candidate factors. Obp2 (Olig2-binding protein 2) has putative RNA helicase domain and thought to be involved in transcriptional regulation. In situ hybridization showed that Obp2 expression was ubiquitous, but was relatively high level in neural progenitor cells of mouse brains and spinal cords. Nestin-Cre: Obp2 conditional knockout (Obp2 cKO) mice died immediately after birth. The Obp2 cKO mice demonstrated that the expression of oligodendrocytic genes was drastically down-regulated in the spinal cords at E17.5. The number of Olig2- and Pdgfrα-positive oligodendrocyte precursor cells started to decrease significantly in Obp2-deficient spinal cords at from E13.5, when oligodendrogenesis is predominant in pMN domain. On the other hand, Obp2 deficiency did not affect motoneuron generation. Thus, these results suggest that Obp2 is a key regulator for Olig2-mediated oligodendrocyte development. 2S2-3 Roles of oligodendrocyte-neuron interactions in myelination Takeshi Shimizu1,2，Yasuyuki Osanai1,2,3，Kazuhiro Ikenaka1,2 1Div of Neurobiol and Bioinfo, Natl Inst for Physiol Sci，2Dept of Physiol Sci, School of Life Sci, SOKENDAI，3Australian Regenerative Med Inst, Monash Univ Our previous study indicated that some populations of oligodendrocytes (OLs) predominantly ensheathed axons derived from a particular brain region, while others evenly myelinated axons from multiple brain regions, suggesting the presence of OL heterogeneity in preference for myelination toward axons from a particular brain region. We also reported that average diameter of myelin internodes formed by individual OLs was divergent. The majority of OLs exclusively formed either large caliber myelin internodes or small caliber myelin internodes. Although molecular mechanisms underlying the region-dependent and axon diameter-specific myelination have yet to be elucidated, the physical properties might influence the myelination. Immature OLs extend their processes onto axon tracts to selectively recognize and sort large diameter axons. During this recognition and subsequent myelination, OLs change their morphology depending on the axon diameter and its kinetics, leading to the generation of mechanical stresses. In addition, when OL precursors reach the axon tracts, which are dynamic and more rigid than the other extracellular environment, they start to differentiate, suggesting that direct interactions between OLs and axons could generate some mechanical factors. We found that mechanical stresses modulated the subcellular localization of a mechanosensor/mechanotransducer YAP, and affected OL morphology via YAP activity. Activation of YAP-dependent mechanotransduction in mouse OL lineages functions in their morphogenesis and maturation in the white matter in vivo. These results indicate that myelination is tightly controlled by OL-neuron signaling that regulates OL differentiation, morphology and myelin formation. 2S2-4 Oligodendrocyte is a dynamic modulator of conduction velocity Kenji Tanaka1，Yoshihiko Yamazaki2 1Dept Neuropsychiatry, Keio Univ Sch Med，2Dept Physiol, Yamagata Univ Sch Med Oligodendrocytes and myelin, which constitute the white matter in the central nervous system, can respond to neuronal activity with prolonged depolarization of membrane potential and/or an increase in the intracellular Ca concentration. Depolarization of oligodendrocytes increases the conduction velocity of an action potential along axons myelinated by the depolarized oligodendrocytes, indicating that white matter shows functional plasticity, as well as structural plasticity. However, the properties and mechanism of oligodendrocyte depolarization-induced functional plastic changes in white matter are largely unknown. Here, we investigated the functional plasticity of white matter in the hippocampus using mice with oligodendrocytes expressing channelrhodopsin-2. Using extracellular recordings of compound action potentials at the alveus of the hippocampus, we demonstrated that light-evoked depolarization of oligodendrocytes induced early- and late-onset facilitation of axonal conduction that was dependent on the magnitude of oligodendrocyte depolarization. These active roles may be accountable for plastic changes in white matter in relation to normal cognitive function and learning. 2S2-5 Up-to-date knowledge on pathomechanism of MS and related disorders Izumi Kawachi，Masatoyo Nishizawa，Osamu Onodera Dept Neurol., Brain Research Institute, Niigata Univ Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune demyelinating diseases of the central nervous system (CNS), having distinct immunological and pathological features: 1) NMO is an autoimmune channelopathy/astrocytopathy that targets the water channel aquaporin-4 (AQP4) on astrocytes in the CNS and AQP4 antibody is a serum diagnostic biomarker for NMO, whereas MS is a disease primarily affecting myelin and oligodendrocytes (oligodendrocytopathy), but no MS-specific autoantigen has been identified. The different aspect of immunological/inflammatory processes between NMO and MS is supported by the observation that some of the anti-inflammatory treatments (type 1 interferons, natalizumab or fingolimod) that are highly effective in patient with MS fail in NMO or may even amplify the disease; and 2) the cytodegenerative processes are also distinct between NMO and MS. Astrocyte loss caused by AQP4 antibody via complement-dependent cytotoxicity may augment excitotoxic neuronal or axonal damage and form acute focal neurodegeneration, whereas chronic and diffuse demyelination and astrocyte activation may be involved in chronic progressive neurodegeneration in MS. These findings are consistent with a new concept in which the CNS autoimmune diseases, MS and NMO, have their distinct immunological dynamics and unique axo-glial pathologies.