Myelination: Actin Disassembly Leads the Way
2015; Elsevier BV; Volume: 34; Issue: 2 Linguagem: Inglês
10.1016/j.devcel.2015.07.006
ISSN1878-1551
AutoresJayshree Samanta, James L. Salzer,
Tópico(s)RNA Research and Splicing
ResumoThe mechanisms that drive the spiral wrapping of the myelin sheath around axons are poorly understood. Two papers in this issue of Developmental Cell demonstrate that actin disassembly, rather than actin assembly, predominates during oligodendrocyte maturation and is critical for the genesis of the central myelin sheath. The mechanisms that drive the spiral wrapping of the myelin sheath around axons are poorly understood. Two papers in this issue of Developmental Cell demonstrate that actin disassembly, rather than actin assembly, predominates during oligodendrocyte maturation and is critical for the genesis of the central myelin sheath. The myelin sheath is essential for rapid conduction of action potentials along nerve fibers and is therefore critical for proper communication of neurons with each other and with their somatic targets. Myelin is also one of the most striking cellular specializations in all of biology. In the CNS, myelin is generated by oligodendrocytes, which contact and then ensheath and wrap around axons. The earliest electron micrographs of the process strongly suggested that myelin forms by circumnavigation of an inner glial membrane sequentially around an axon, which then compacts by excluding cytoplasm from between the membrane wraps (lamellae) (Bunge, 1968Bunge R.P. Physiol. Rev. 1968; 48: 197-251PubMed Google Scholar). Support for this notion was provided by a recent study demonstrating that myelin indeed grows by expansion of its inner turn and by extending along its lateral margins (Snaidero et al., 2014Snaidero N. Möbius W. Czopka T. Hekking L.H. Mathisen C. Verkleij D. Goebbels S. Edgar J. Merkler D. Lyons D.A. et al.Cell. 2014; 156: 277-290Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). A major, unanswered question is what drives the rapid, circumferential spiraling of the inner glial membrane around an axon to generate the myelin sheath. The inner turn must extend into the space between the glial cell and the axon, disrupting existing interactions (Figure 1), strongly suggesting that mechanical force is required. In this issue of Developmental Cell, Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar and Nawaz et al., 2015Nawaz S. Sánchez P. Schmitt S. Snaidero N. Mitkovski M. Velte C. Brückner B.R. Alexopoulos I. Czopka T. Jung S.Y. et al.Dev. Cell. 2015; 34 (this issue): 139-151Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar provide major new insights into this process. Using complementary approaches, they demonstrate that dynamic actin remodeling—in particular actin disassembly—is critical for myelin sheath formation. The involvement of the actin cytoskeleton in myelination is consistent with the key role of actin in other morphogenetic events, notably cell motility (Blanchoin et al., 2014Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (797) Google Scholar). In motile cells, branched and crosslinked actin networks provide the major engine for movement of the lamellipodium/leading edge by polymerizing against it and driving protrusion (Blanchoin et al., 2014Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (797) Google Scholar). Actin is dynamically remodeled during this protrusion by both polymerizing/nucleating factors (such as members of the WASP [Wiskott-Aldrich syndrome protein] family), which regulate the Arp2/3 (Actin-Related Proteins) complex, and depolymerizing factors (e.g., gelsolin and ADF/cofilin family members), which break down actin behind the front and free actin monomers (G-actin) for reassembly. Actin-independent modes of cell motility also occur, notably "bleb expansion," in which protrusion of the cell membrane is driven by hydrostatic pressure generated within the cytoplasm by contractile actomyosin forces (Paluch and Raz, 2013Paluch E.K. Raz E. Curr. Opin. Cell Biol. 2013; 25: 582-590Crossref PubMed Scopus (228) Google Scholar). While glial cells are stationary during myelination, extension of their inner membrane around an axon can be likened to the leading edge of a migrating cell. Indeed, actin has previously been implicated in Schwann cell myelination (Fernandez-Valle et al., 1997Fernandez-Valle C. Gorman D. Gomez A.M. Bunge M.B. J. Neurosci. 1997; 17: 241-250Crossref PubMed Google Scholar) notably by conditional ablation of N-WASP, which results in profound defects (Jin et al., 2011Jin F. Dong B. Georgiou J. Jiang Q. Zhang J. Bharioke A. Qiu F. Lommel S. Feltri M.L. Wrabetz L. et al.Development. 2011; 138: 1329-1337Crossref PubMed Scopus (51) Google Scholar, Novak et al., 2011Novak N. Bar V. Sabanay H. Frechter S. Jaegle M. Snapper S.B. Meijer D. Peles E. J. Cell Biol. 2011; 192: 243-250Crossref PubMed Scopus (64) Google Scholar). A previous report also found that WAVE1, a member of the WASP family, contributes to oligodendrocyte myelination (Kim et al., 2006Kim H.J. DiBernardo A.B. Sloane J.A. Rasband M.N. Solomon D. Kosaras B. Kwak S.P. Vartanian T.K. J. Neurosci. 2006; 26: 5849-5859Crossref PubMed Scopus (78) Google Scholar). However, the organization and dynamic regulation of actin during oligodendrocyte myelination has been poorly understood to this point. Nawaz et al., 2015Nawaz S. Sánchez P. Schmitt S. Snaidero N. Mitkovski M. Velte C. Brückner B.R. Alexopoulos I. Czopka T. Jung S.Y. et al.Dev. Cell. 2015; 34 (this issue): 139-151Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar and Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar now systematically characterize and perturb the dynamic state of the actin cytoskeleton during oligodendrocyte maturation and myelination in cultures and in vivo. Both groups found that F-actin levels were markedly reduced in white matter as myelination progressed. These findings were compellingly underscored at the cellular level in elegant live imaging studies in developing zebrafish. Using Lifeact-RFP as an F-actin reporter, Nawaz et al. show that F-actin is first broadly expressed by oligodendrocytes, then confined to a thin spiral presumptively corresponding to the leading edge of wrapping oligodendrocytes. When myelination is complete, F-actin is lost along the inner turn, although retained at the lateral edges. Thus, oligodendrocytes undergo a transition from actin assembly during initial process elaboration and axon engagement to actin disassembly during active myelination. A similar transition occurs during oligodendrocyte maturation in vitro, which permits better resolution of dynamic F-actin changes due to oligodendrocytes' flat membrane topology in culture. Both groups found that F-actin is initially abundant, but over time becomes concentrated at the rim of the cell (taken as the leading edge) and is lost or displaced from the flattened, intervening myelin basic protein (MBP)-positive membrane sheets (likely to correspond to membranes of the myelin lamellae) before being lost completely. Because total actin levels do not change, these results again demonstrate a transition from F-actin to G-actin with maturation. Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar directly address the role of actin assembly during myelination by inhibiting the Arp2/3 complex. Components of the complex are enriched at the edge of cultured oligodendrocytes, in agreement with a similar localization of WAVE, an upstream regulator of Arp2/3 (Kim et al., 2006Kim H.J. DiBernardo A.B. Sloane J.A. Rasband M.N. Solomon D. Kosaras B. Kwak S.P. Vartanian T.K. J. Neurosci. 2006; 26: 5849-5859Crossref PubMed Scopus (78) Google Scholar). Loss of Arp2/3 activity early in the oligodendroglial lineage impairs ensheathment and myelination of axons, supporting a role for F-actin during initial axon engagement. Unexpectedly, conditional ablation of Arp2/3 function during active myelination did not impede further myelination. In an imaginative variation, Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar ablated Arp2/3 function in the adult while simultaneously eliminating PTEN, which is known to reactivate myelin wrapping (Snaidero et al., 2014Snaidero N. Möbius W. Czopka T. Hekking L.H. Mathisen C. Verkleij D. Goebbels S. Edgar J. Merkler D. Lyons D.A. et al.Cell. 2014; 156: 277-290Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). They found that additional myelin wrapping occurred despite loss of Arp2/3. These results indicate that, unless Arp2/3 activity perdures after ablation or there are other as-yet-unknown compensating nucleating factors, actin assembly is surprisingly dispensable during myelination. Both groups next addressed the role of actin disassembly during myelination. Consistent with a transition to G-actin, RNA-seq data indicate that actin depolymerizing proteins are markedly upregulated in myelinating oligodendrocytes (Zhang et al., 2014Zhang Y. Chen K. Sloan S.A. Bennett M.L. Scholze A.R. O'Keeffe S. Phatnani H.P. Guarnieri P. Caneda C. Ruderisch N. et al.J. Neurosci. 2014; 34: 11929-11947Crossref PubMed Scopus (2923) Google Scholar). Zuchero et al. explore an additional mechanism that may contribute to actin depolymerization—competitive binding of MBP to PI(4,5)P2 on the inner leaflet of the membrane sheets—which is predicted to displace and thereby activate several depolymerizing proteins. Both groups observed that treating cultured oligodendrocytes with latrunculin A, thus depolymerizing actin, is accompanied by a striking increase in the flattened membrane regions. Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar further show that treatment with latrunculin A during in vivo development promoted myelination, increasing the resultant numbers of myelin lamellae. Both groups then characterized myelination in mice deficient in one or more actin depolymerizing proteins, an analysis complicated by the redundancy of depolymerizing components. In Nawaz et al., 2015Nawaz S. Sánchez P. Schmitt S. Snaidero N. Mitkovski M. Velte C. Brückner B.R. Alexopoulos I. Czopka T. Jung S.Y. et al.Dev. Cell. 2015; 34 (this issue): 139-151Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, a conditional oligodendrocyte knockout of cofilin1 combined with a pan-ADF knockout resulted in persistence of F-actin, notably in the inner turn, and a concomitant decrease in overall myelination. Similarly, Zuchero et al., 2015Zuchero J.B. Meng-meng F. Sloan S.A. Ibrahim A. Olson A. Zaremba A. Dugas J.C. Wienbar S. Caprariello A.V. Kantor C. et al.Dev. Cell. 2015; 34 (this issue): 152-167Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar found a small but significant reduction in myelin thickness in the optic nerves of gelsolin null mice. Taken together, these results strongly indicate that actin disassembly promotes myelin sheath formation. A key question is how actin depolymerization drives myelin sheath formation. Nawaz et al., 2015Nawaz S. Sánchez P. Schmitt S. Snaidero N. Mitkovski M. Velte C. Brückner B.R. Alexopoulos I. Czopka T. Jung S.Y. et al.Dev. Cell. 2015; 34 (this issue): 139-151Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar use laser trap and atomic force microscopy to show that loss of F-actin results in reduced membrane tension, facilitating membrane spreading and cell attachment, providing an additional mechanism for membrane expansion in the absence of actin. In contrast, the leading edge of oligodendrocytes, which is enriched in F-actin, has increased membrane tension and reduced adhesion, promoting its extension. These studies together highlight a major and unexpected role of actin disassembly during myelination. A key question, and one on which the studies diverge, is what drives the protrusion of the leading edge. Is it F-actin-dependent, as suggested by the live imaging in Nawaz et al., which appears to show F-actin at the leading edge during myelin formation? Or is it F-actin-independent, as suggested by Zuchero et al., who show that myelination proceeds in the absence of Arp2/3 function? In Nawaz et al., actin disassembly both facilitates membrane spreading and supports an iterative cycle of polymerization/depolymerization to generate an actin network at the leading edge that drives its protrusion. In contrast, Zuchero et al. suggest that forward propulsion of the leading edge is independent of actin polymerization and may be driven by increased hydrostatic pressure within the cell, which potentially builds up by zippering membrane sheets driven by MBP rather than via actomyosin contractility. Clarifying these distinct models, including whether both mechanisms of protrusion occur at different stages of myelination, promises additional critical insights into the genesis of this remarkable structure. Actin Filament Turnover Drives Leading Edge Growth during Myelin Sheath Formation in the Central Nervous SystemNawaz et al.Developmental CellJuly 9, 2015In BriefOligodendrocytes wrap their plasma membrane around axons to generate multilamellar myelin sheaths, but the molecular machinery that drives growth has not been identified. Nawaz and Sánchez et al. show that F-actin turnover is the driving force in myelin wrapping by regulating repetitive cycles of leading edge protrusion and spreading. Full-Text PDF Open ArchiveCNS Myelin Wrapping Is Driven by Actin DisassemblyZuchero et al.Developmental CellJuly 9, 2015In BriefOligodendrocytes form CNS myelin by ensheathing axons and then spirally wrapping around them. Zuchero et al. show that myelination requires actin dynamics in two steps: Arp2/3-dependent actin assembly powers oligodendrocyte process outgrowth to ensheath axons, and then disassembly of the actin cytoskeleton drives myelin wrapping. Full-Text PDF Open Archive
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