Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

Akiyama, Masahiro; Hasegawa, Hiroshi; Hongu, Tsunaki; Frohman, Michael A.; Harada, Akira; Sakagami, Hiroyuki; Kanaho, Yasunori

doi:10.1038/ncomms5744

Cited by 27 publications

(24 citation statements)

References 37 publications

(43 reference statements)

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“…It was also recently reported that neurons contribute to the regulation of oligodendrocyte myelination through the expression of GTPase Arf6, which controls the secretion of FGF-2. In mice with Arf6 knocked out specifically in neurons, secretion of FGF-2 was reduced and myelination was abnormal (Akiyama et al, 2014). …”

Section: Factors Affecting Remyelination After Strokementioning

confidence: 99%

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

et al. 2015

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White matter damage is a clinically important aspect of several central nervous system diseases, including stroke. Cerebral white matter primarily consists of axonal bundles ensheathed with myelin secreted by mature oligodendrocytes, which play an important role in neurotransmission between different areas of gray matter. During the acute phase of stroke, damage to oligodendrocytes leads to white matter dysfunction through the loss of myelin. On the contrary, during the chronic phase, white matter components promote an environment, which is favorable for neural repair, vascular remodeling, and remyelination. For effective remyelination to take place, oligodendrocyte precursor cells (OPCs) play critical roles by proliferating and differentiating into mature oligodendrocytes, which help to decrease the burden of axonal injury. Notably, other types of cells contribute to these OPC responses under the ischemic conditions. This mini-review summarizes the non-cell autonomous mechanisms in oligodendrogenesis and remyelination after white matter damage, focusing on how OPCs receive support from their neighboring cells.

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Section: Factors Affecting Remyelination After Strokementioning

confidence: 99%

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

et al. 2015

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“…Arf6 flox/flox mice 26 were crossed with PF4-promoter-driven Cre-recombinase transgenic mice (Dr Radek Skoda, University Hospital, Basel, Switzerland). 27 Each animal was genotyped by polymerase chain reaction using DNA from tail biopsies.…”

Section: Mouse Generation and Genotypingmentioning

confidence: 99%

Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

Huang¹,

Joshi²,

Xiang

et al. 2016

Blood

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• Arf6 selectively regulates endocytic trafficking of platelet a IIb b 3 .• Endocytosis contributes to acute platelet function.Platelet and megakaryocyte endocytosis is important for loading certain granule cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor); however, the mechanisms of platelet endocytosis and its functional acute effects are understudied. Adenosine 5'-diphosphate-ribosylation factor 6 (Arf6) is a small guanosine triphosphate-binding protein that regulates endocytic trafficking, especially of integrins. To study platelet endocytosis, we generated platelet-specific Arf6 knockout (KO) mice. Arf6 KO platelets had less associated Fg suggesting that Arf6 affects a IIb b 3 -mediated Fg uptake and/or storage. Other cargo was unaffected. To measure Fg uptake, mice were injected with biotinylated-or fluorescein isothiocyanate (FITC)-labeled Fg. Platelets from the injected Arf6 KO mice showed lower accumulation of tagged Fg, suggesting an uptake defect. Ex vivo, Arf6 KO platelets were also defective in FITC-Fg uptake and storage. Immunofluorescence analysis showed initial trafficking of FITC-Fg to a Rab4-positive compartment followed by colocalization with Rab11-positive structures, suggesting that platelets contain and use both early and recycling endosomes. Resting and activated a IIb b 3 levels, as measured by flow cytometry, were unchanged; yet, Arf6 KO platelets exhibited enhanced spreading on Fg and faster clot retraction. This was not the result of alterations in a IIb b 3 signaling, because myosin light-chain phosphorylation and Rac1/RhoA activation were unaffected. Consistent with the enhanced clot retraction and spreading, Arf6 KO mice showed no deficits in tail bleeding or FeCl 3 -induced carotid injury assays. Our studies present the first mouse model for defining the functions of platelet endocytosis and suggest that altered integrin trafficking may affect the efficacy of platelet function. (Blood. 2016;127(11):1459-1467 IntroductionIt is increasingly clear that platelets are capable of different types of intracellular membrane trafficking. Platelet exocytosis and autophagy are critical for hemostasis. [1][2][3][4] Platelet endocytosis is important for granule cargo loading. Platelets selectively take up certain cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor) from plasma and package it into a-granules. [5][6][7][8] However, the molecular mechanisms of platelet endocytosis are largely unknown. It is also unclear whether platelet endocytosis contributes to acute platelet functions beyond granule cargo loading. The goal of this study is to begin to address these fundamental questions.The Ras-like, small guanosine triphosphate (GTP)-binding proteins called adenosine 5'-diphosphate-ribosylation factors (Arf's), are key intracellular trafficking regulators. They cycle between inactive guanosine diphosphate (GDP)-bound and active GTP-bound states and are important for multiple functions (eg, actin cytoskeleton remodeling, lipid metabolism, and vesicle traffickin...

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“…22 In that study, we employed CNP-Cre mice to produce O-Arf6-CKO mice which did not show any abnormality in axon myelination, suggesting that Arf6 in OPCs/oligodendrocytes is dispensable for myelination. Considering that efficiency of Cre-mediated recombination in OPCs is about 50%, 35 however, we cannot totally rule out the possibility that Arf6 expressed in OPCs/oligodendrocytes is also involved in myelination: if Arf6 in OPCs/oligodendrocytes is completely knocked out, defect in axon myelination may be induced.…”

Section: Please Scroll Down For Articlementioning

confidence: 98%

“…1). 22 FGF-2 is secreted through the unconventional secretion pathway in which FGF-2 is directly translocated across the plasma membrane. In this pathway, phosphatidylinositol 4,5-bisphosphate (PI4,5P 2 ) locally synthesized at the plasma membrane directly binds to FGF-2 to trigger its secretion.…”

Section: Please Scroll Down For Articlementioning

confidence: 99%

Physiological functions of the small GTPase Arf6 in the nervous system

Akiyama

Kanaho

2015

Small GTPases

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The small GTPase ADP-ribosylation factor 6 (Arf6) plays important roles in membrane dynamics-based neuronal cell events such as neurite outgrowth and spine formation. However, physiological functions of Arf6 in the nervous system at whole animal level have not yet been explored. We have recently generated conditional knockout mice lacking Arf6 in neurons or oligodendrocytes of central nervous system (CNS) or both cell lineages, and analyzed them. We found that ablation of Arf6 gene from neurons, but not from oligodendrocytes, caused the defect in axon myelination at the fimbria of hippocampus (Fim) and corpus callosum (CC). We also found that migration of oligodendrocyte precursor cells (OPCs) from the subventricular zone to the Fim and CC in mice lacking Arf6 in neurons was impaired. Finally, it was found that secretion of fibroblast growth factor-2 (FGF-2), a guidance factor for OPC migration, from hippocampi lacking Arf6 was impaired. Collectively, these findings demonstrate that Arf6 in neurons of the CNS plays an important role in OPC migration by regulating secretion of FGF-2 from neurons, thereby contributing to the axon myelination. Here, we discuss our current understanding of physiological functions of Arf6 in the nervous system.

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Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

Cited by 27 publications

References 37 publications

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

Arf6 controls platelet spreading and clot retraction via integrin αIIbβ3 trafficking

Physiological functions of the small GTPase Arf6 in the nervous system

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