Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination

Miyamoto, Yuki; Torii, Tomohiro; Takada, Shuji; Ohno, Nobuhiko; Saitoh, Yurika; Nakamura, Kazuaki; Ito, Akihito; Ogata, Toru; Terada, Nobuo; Tanoue, Akito; Yamauchi, Junji

doi:10.1091/mbc.e14-05-1020

Cited by 26 publications

(26 citation statements)

References 47 publications

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“…In addition to the delay in the initiation of myelination in the absence of Tyro3, we have identified alterations in the thickness of myelin ensheathing axons in both the optic nerve and in the corpus callosum. These observations complement a recently published study in which Tyro3 deficiency was associated with a reduction in the thickness of myelin produced by Schwann cells (Miyamoto et al, ). In combination, these observations indicate that Tyro3 is important for the regulation of both CNS and PNS myelination.…”

Section: Discussionsupporting

confidence: 91%

“…Tyro3 is widely expressed in the CNS, particularly in developing white matter tracts (Prieto et al, 2000), although its function in the CNS remains largely unknown. In contrast, in the peripheral nervous system, Tyro3 was recently reported to regulate myelin sheath thickness by Schwann cells (Miyamoto et al, 2015). All three TAM receptors are expressed on OPCs, but whereas Axl and Mertk are subsequently absent from the lineage, Tyro3 is highly upregulated on newly formed and mature myelinating oligodendrocytes (Binder et al, 2008;Cahoy et al, 2008;Nielsen et al, 2006) and Tyro3 expression is lost upon genetic ablation of oligodendrocytes (Golan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The TAM receptor Tyro3 regulates myelination in the central nervous system

Akkermann

Aprico

Perera

et al. 2017

Glia

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Myelin is an essential component of the mammalian nervous system, facilitating rapid conduction of electrical impulses by axons, as well as providing trophic support to neurons. Within the central nervous system, the oligodendrocyte is the specialized neural cell responsible for producing myelin by a process that is thought to be regulated by both activity dependent and independent mechanisms but in incompletely understood ways. We have previously identified that the protein Gas6, a ligand for a family of tyrosine kinase receptors known as the TAM (Tyro3, Axl, and Mertk) receptors, directly increases oligodendrocyte induced myelination in vitro. Gas6 can bind to and activate all three TAM receptors, but the high level of expression of Tyro3 on oligodendrocytes makes this receptor the principal candidate for transducing the pro-myelinating effect of Gas6. In this study, we establish that in the absence of Tyro3, the pro-myelinating effect of Gas6 is lost, that developmental myelination is delayed and that the myelin produced is thinner than normal. We show that this effect is specific to the myelination process and not due to changes in the proliferation or differentiation of oligodendrocyte precursor cells. We have further demonstrated that the reduction in myelination is due to the loss of Tyro3 on oligodendrocytes, and this effect may be mediated by activation of Erk1. Collectively, our findings indicate the critical importance of Tyro3 in potentiating central nervous system myelination. GLIA 2017 GLIA 2017;65:581-591.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The TAM receptor Tyro3 regulates myelination in the central nervous system

Akkermann

Aprico

Perera

et al. 2017

Glia

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“…Thus, Gas6 stimulated a higher activation state of Tyro3 after 3 h in the optic nerve, as observed by increased p-Tyro3 protein levels. This observation is supported by a recent study in the peripheral nervous system that showed Tyro3 to be an important modulator of myelination by Schwann cells ( Miyamoto et al., 2015 ).…”

Section: Discussionsupporting

confidence: 69%

Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination

et al. 2016

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A key aim of therapy for multiple sclerosis (MS) is to promote the regeneration of oligodendrocytes and remyelination in the central nervous system (CNS). The present study provides evidence that the vitamin K-dependent protein growth arrest specific 6 (Gas6) promotes such repair in in vitro cultures of mouse optic nerve and cerebellum. We first determined expression of Gas6 and TAM (Tyro3, Axl, Mer) receptors in the mouse CNS, with all three TAM receptors increasing in expression through postnatal development, reaching maximal levels in the adult. Treatment of cultured mouse optic nerves with Gas6 resulted in significant increases in oligodendrocyte numbers as well as expression of myelin basic protein (MBP). Gas6 stimulation also resulted in activation of STAT3 in optic nerves as well as downregulation of multiple genes involved in MS development, including matrix metalloproteinase-9 (MMP9), which may decrease the integrity of the blood–brain barrier and is found upregulated in MS lesions. The cytoprotective effects of Gas6 were examined in in vitro mouse cerebellar slice cultures, where lysolecithin was used to induce demyelination. Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation. In conclusion, these results demonstrate that Gas6/TAM signaling stimulates the generation of oligodendrocytes and increased myelin production via Tyro3 receptor in the adult CNS, including repair after demyelinating injury. Furthermore, the effects of Gas6 on STAT3 signaling and matrix MMP9 downregulation indicate potential glial cell repair and immunoregulatory roles for Gas6, indicating that Gas6-TAM signaling could be a potential therapeutic target in MS and other neuropathologies.

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“…Remyelination by oligodendrocytes is regulated by both intrinsic mechanisms and extrinsic factors from cells surrounding oligodendrocytes (Miron et al, 2011;Boulanger and Messier, 2014;El Waly et al, 2014;Tanaka and Yoshida, 2014), in the same manner as myelination by Schwann cells (Yamauchi et al, 2012;Miyamoto et al, 2015). Astrocytes function as cellular mediators of myelination and remyelination of oligodendrocytes by releasing various factors (PDGF, FGF2, CNTF, LIF, extracellular matrix-related molecules, etc.)…”

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confidence: 99%

Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation

Ichihara

Doi

Ryu

et al. 2016

Journal Cellular Physiology

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Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4‐dideoxy‐1,4‐imino‐d‐arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC‐rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU‐positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate‐mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α‐cyano‐4‐hydroxy‐cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986–995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination

Cited by 26 publications

References 47 publications

The TAM receptor Tyro3 regulates myelination in the central nervous system

The TAM receptor Tyro3 regulates myelination in the central nervous system

Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination

Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation

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