Rho Regulates Membrane Transport in the Endocytic Pathway to Control Plasma Membrane Specialization in Oligodendroglial Cells

Kippert, Angelika; Trajković, Katarina; Rajendran, Lawrence; Ries, Jonas; Simons, Mikael

doi:10.1523/jneurosci.4926-06.2007

Cited by 50 publications

(52 citation statements)

References 63 publications

(69 reference statements)

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“…LE/Lys localization of PLP and VAMP7 is consistent with the literature (Advani et al, 1999;Krämer et al, 2001;Feldmann et al, 2009). It has been shown that PLP accumulates in LE/Lys on clathrin-independent cholesterol-dependent endocytosis, and furthermore, retranslocation of PLP from LE/Lys storage sites to the plasma membrane is regulated by RhoGTPase inactivation triggered by a soluble neuronal signal Kippert et al, 2007). Recycling through LE/Lys facilitates association of PLP with membranes exhibiting specific myelin characteristics (Winterstein et al, 2008).…”

Section: Discussionsupporting

confidence: 88%

“…There is accumulating evidence that oligodendrocytes, which simultaneously assemble myelin sheaths at multiple subcellular sites, use endosomes as local internal membrane sorting and storage compartments, from which membrane is rapidly recruited to the sites of membrane growth controlled by neuronal signaling Kippert et al, 2007;Winterstein et al, 2008). Our study demonstrates that VAMP3 and VAMP7 mediate surface delivery from RE and LE/Lys, respectively.…”

Section: Role Of Vamp3 and Vamp7 In Myelinationmentioning

confidence: 69%

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Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Feldmann¹,

Amphornrat²,

Schönherr³

et al. 2011

J. Neurosci.

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CNS myelination by oligodendrocytes requires directed transport of myelin membrane components and a timely and spatially controlled membrane expansion. In this study, we show the functional involvement of the R-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE) proteins VAMP3/cellubrevin and VAMP7/TI-VAMP in myelin membrane trafficking. VAMP3 and VAMP7 colocalize with the major myelin proteolipid protein (PLP) in recycling endosomes and late endosomes/lysosomes, respectively. Interference with VAMP3 or VAMP7 function using small interfering RNA-mediated silencing and exogenous expression of dominantnegative proteins diminished transport of PLP to the oligodendroglial cell surface. In addition, the association of PLP with myelin-like membranes produced by oligodendrocytes cocultured with cortical neurons was reduced. We furthermore identified Syntaxin-4 and Syntaxin-3 as prime acceptor Q-SNAREs of VAMP3 and VAMP7, respectively. Analysis of VAMP3-deficient mice revealed no myelination defects. Interestingly, AP-3␦-deficient mocha mice, which suffer from impaired secretion of lysosome-related organelles and missorting of VAMP7, exhibit a mild dysmyelination characterized by reduced levels of select myelin proteins, including PLP. We conclude that PLP reaches the cell surface via at least two trafficking pathways with distinct regulations: (1) VAMP3 mediates fusion of recycling endosomederived vesicles with the oligodendroglial plasma membrane in the course of the secretory pathway; (2) VAMP7 controls exocytosis of PLP from late endosomal/lysosomal organelles as part of a transcytosis pathway. Our in vivo data suggest that exocytosis of lysosomerelated organelles controlled by VAMP7 contributes to myelin biogenesis by delivering cargo to the myelin membrane.

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Section: Discussionsupporting

confidence: 88%

Section: Role Of Vamp3 and Vamp7 In Myelinationmentioning

confidence: 69%

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Feldmann¹,

Amphornrat²,

Schönherr³

et al. 2011

J. Neurosci.

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“…Of interest, a similar correlation between downregulation of acto-myosin contractility and membrane extension has been recently described during morphological differentiation of oligodendrocytes (Kippert et al, 2009), suggesting that despite their different morphologies and modes of myelination, the mechanisms controlling plasma membrane expansion by myelinating glial cells require local release of myosin-II-mediated contraction and relaxation of the actin cytoskeleton. Whether MLCK activity also plays a role in oligodendrocyte remodeling and differentiation awaits further study, but inactivation of RhoA and ROCK as well as inhibition of myosin II have been shown to promote membrane expansion and oligodendrocyte branching and differentiation (Kippert et al, 2007;Wang et al, 2008;Wolf et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination

Leitman

Tewari

Horn

et al. 2011

Journal of Cell Science

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SummarySignaling through cyclic AMP (cAMP) has been implicated in the regulation of Schwann cell (SC) proliferation and differentiation. In quiescent SCs, elevation of cAMP promotes the expression of proteins associated with myelination such as Krox-20 and P0, and downregulation of markers associated with the non-myelinating SC phenotype. We have previously shown that the motor protein myosin II is required for the establishment of normal SC-axon interactions, differentiation and myelination, however, the mechanisms behind these effects are unknown. Here we report that the levels and activity of myosin light chain kinase (MLCK), an enzyme that regulates MLC phosphorylation in non-muscle cells, are dramatically downregulated in SCs after cAMP treatment, in a similar pattern to that of c-Jun, a known inhibitor of myelination. Knockdown of MLCK in SCs mimics the effect of cAMP elevation, inducing plasma membrane expansion and expression of Krox-20 and myelin proteins. Despite activation of myelin gene transcription these cells fail to make compact myelin when placed in contact with axons. Our data indicate that myosin II activity is differentially regulated at various stages during myelination and that in the absence of MLCK the processes of SC differentiation and compact myelin assembly are uncoupled.

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“…It has been demonstrated recently that soluble factors secreted from neurons induce a reduction in clathrinindependent endocytosis and a stimulation of exocytosis of PLP in cultured oligodendrocytes, which is regulated by Rho-GTPase activity levels (Kippert et al, 2007;Trajkovic et al, 2006). Thus, neuron-to-glia signaling regulates endocytic trafficking of the major myelin protein allowing target-oriented tuning of myelin membrane traffic.…”

Section: Journal Of Cell Science 121 (6) Endocytic Trafficking Of Myementioning

confidence: 99%

Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling

Winterstein

Trotter

Krämer-Albers

2008

Journal of Cell Science

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The central nervous system myelin sheath is a multilayered specialized membrane with compacted and non-compacted domains of defined protein composition. How oligodendrocytes regulate myelin membrane trafficking and establish membrane domains during myelination is largely unknown. Oligodendroglial cells respond to neuronal signals by adjusting the relative levels of endocytosis and exocytosis of the major myelin protein, proteolipid protein (PLP). We investigated whether endocytic trafficking is common to myelin proteins and analyzed the endocytic fates of proteins with distinct myelin subdomain localization. Interestingly, we found that PLP, myelin-associated glycoprotein (MAG) and myelin-oligodendrocyte glycoprotein (MOG), which localize to compact myelin, periaxonal loops and abaxonal loops, respectively, exhibit distinct endocytic fates. PLP was internalized via clathrin-independent endocytosis, whereas MAG was endocytosed by a clathrin-dependent pathway, although both proteins were targeted to the late-endosomal/lysosomal compartment. MOG was also endocytosed by a clathrin-dependent pathway, but in contrast to MAG, trafficked to the recycling endosome. Endocytic recycling resulted in the association of PLP, MAG and MOG with oligodendroglial membrane domains mimicking the biochemical characteristics of myelin domains. Our results suggest that endocytic sorting and recycling of myelin proteins may assist plasma membrane remodeling, which is necessary for the morphogenesis of myelin subdomains.

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Rho Regulates Membrane Transport in the Endocytic Pathway to Control Plasma Membrane Specialization in Oligodendroglial Cells

Cited by 50 publications

References 63 publications

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination

Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling

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