Key points are not available for this paper at this time.
Myelin formation is a multistep process that is controlled by a number of different extracellular factors. During the development of the central nervous system (CNS), oligodendrocyte progenitor cells differentiate into mature oligodendrocytes that start to enwrap axons with myelin membrane sheaths after receiving the appropriate signal(s) from the axon or its microenvironment. The signals required to initiate this process are unknown. Here, we show that oligodendrocytes secrete small membrane vesicles, exosome-like vesicles, into the extracellular space that inhibit both the morphological differentiation of oligodendrocytes and myelin formation. The inhibitory effects of exosome-like vesicles were prevented by treatment with inhibitors of actomyosin contractility. Importantly, secretion of exosome-like vesicles from oligodendrocytes was dramatically reduced when cells were incubated by conditioned neuronal medium.In conclusion, our results provide new evidence for small and diffusible oligodendroglial-derived vesicular carriers within the extracellular space that have inhibitory properties on cellular growth. We propose that neurons control the secretion of autoinhibitory oligodendroglial-derived exosomes to coordinate myelin membrane biogenesis. Myelin formation is a multistep process that is controlled by a number of different extracellular factors. During the development of the central nervous system (CNS), oligodendrocyte progenitor cells differentiate into mature oligodendrocytes that start to enwrap axons with myelin membrane sheaths after receiving the appropriate signal(s) from the axon or its microenvironment. The signals required to initiate this process are unknown. Here, we show that oligodendrocytes secrete small membrane vesicles, exosome-like vesicles, into the extracellular space that inhibit both the morphological differentiation of oligodendrocytes and myelin formation. The inhibitory effects of exosome-like vesicles were prevented by treatment with inhibitors of actomyosin contractility. Importantly, secretion of exosome-like vesicles from oligodendrocytes was dramatically reduced when cells were incubated by conditioned neuronal medium. In conclusion, our results provide new evidence for small and diffusible oligodendroglial-derived vesicular carriers within the extracellular space that have inhibitory properties on cellular growth. We propose that neurons control the secretion of autoinhibitory oligodendroglial-derived exosomes to coordinate myelin membrane biogenesis. IntroductionDuring the development of the CNS, oligodendrocyte precursor cells (OPCs) 2The abbreviations used are: OPColigodendrocyte precursor cellPLPproteolipid proteinPpostnatal dayMBPmyelin basic proteinMVBmultivesicular bodyNCMneuronal conditioned mediumCNPase2′,3′-cyclic nucleotide 3′-phosphodiesteraseMAGmyelin-associated glycoproteinMOGmyelin oligodendrocyte glycoprotein. undergo major changes in cell morphology when they start to differentiate into myelin-forming oligodendrocytes (1Chong S.Y. Chan J.R. J. Cell Biol. 2010; 188: 305-312Crossref PubMed Scopus (44) Google Scholar, 2Richardson W.D. Kessaris N. Pringle N. Nat. Rev. Neurosci. 2006; 7: 11-18Crossref PubMed Scopus (303) Google Scholar, 3Baumann N. Pham-Dinh D. Physiol. Rev. 2001; 81: 871-927Crossref PubMed Scopus (1320) Google Scholar). First, a large network of branching processes is formed, and then oligodendrocytes start to extend massive amounts of myelin membrane sheaths (4Simons M. Trotter J. Curr. Opin Neurobiol. 2007; 17: 533-540Crossref PubMed Scopus (164) Google Scholar, 5Sherman D.L. Brophy P.J. Nat. Rev. Neurosci. 2005; 6: 683-690Crossref PubMed Scopus (485) Google Scholar). The generation of myelinating oligodendrocytes from proliferating, immature OPCs is complex and depends on an intrinsic genetic differentiation program that is regulated in part by an intracellular molecular clock determining how many times an OPC can divide before differentiating (6Temple S. Raff M.C. Cell. 1986; 44: 773-779Abstract Full Text PDF PubMed Scopus (361) Google Scholar, 7Barres B.A. Lazar M.A. Raff M.C. Development. 1994; 120: 1097-1108Crossref PubMed Google Scholar, 8Dugas J.C. Ibrahim A. Barres B.A. J. Neurosci. 2007; 27: 6185-6196Crossref PubMed Scopus (66) Google Scholar). This intrinsic program is under the control of various extrinsic factors present within the microenvironment of oligodendrocytes. Many of these factors such as Notch1, Wnt, LINGO-1 (leucine-rich repeat, and Ig domain-containing, Nogo receptor-interacting protein 1), or the polysialylated neural cell adhesion molecule are inhibitory in nature and prevent OPCs from differentiating into mature oligodendrocytes (9Wang S. Sdrulla A.D. diSibio G. Bush G. Nofziger D. Hicks C. Weinmaster G. Barres B.A. Neuron. 1998; 21: 63-75Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 10Charles P. Hernandez M.P. Stankoff B. Aigrot M.S. Colin C. Rougon G. Zalc B. Lubetzki C. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 7585-7590Crossref PubMed Scopus (241) Google Scholar, 11Mi S. Miller R.H. Lee X. Scott M.L. Shulag-Morskaya S. Shao Z. Chang J. Thill G. Levesque M. Zhang M. Hession C. Sah D. Trapp B. He Z. Jung V. McCoy J.M. Pepinsky R.B. Nat. Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (504) Google Scholar, 12Zhang Y. Argaw A.T. Gurfein B.T. Zameer A. Snyder B.J. Ge C. Lu Q.R. Rowitch D.H. Raine C.S. Brosnan C.F. John G.R. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 19162-19167Crossref PubMed Scopus (158) Google Scholar, 13Fancy S.P. Baranzini S.E. Zhao C. Yuk D.I. Irvine K.A. Kaing S. Sanai N. Franklin R.J. Rowitch D.H. Genes Dev. 2009; 23: 1571-1585Crossref PubMed Scopus (463) Google Scholar, 14Ye F. Chen Y. Hoang T. Montgomery R.L. Zhao X.H. Bu H. Hu T. Taketo M.M. van Es J.H. Clevers H. Hsieh J. Bassel-Duby R. Olson E.N. Lu Q.R. Nat. Neurosci. 2009; 12: 829-838Crossref PubMed Scopus (450) Google Scholar). Down-regulation of these inhibitory cues seems to be an important mechanism in triggering the differentiation of oligodendrocytes. Once differentiation of oligodendrocytes is induced, the cells start to synthesize large amount of myelin membrane components including lipids and several myelin-specific proteins, the major ones of these being the proteolipid protein (PLP) and the myelin basic proteins (MBP). Curiously, the biosynthesis of the major myelin membrane components occurs before the assembly of myelin is initiated, most likely by neuronal factor(s). In fact, such premyelinating oligodendrocytes that have started to synthesize myelin lipids and proteins but have not yet wrapped myelin around axons are only found for a relatively short period during the development of the CNS (15Trapp B.D. Nishiyama A. Cheng D. Macklin W. J. Cell Biol. 1997; 137: 459-468Crossref PubMed Scopus (305) Google Scholar). Importantly, these premyelinating oligodendrocytes seem to separate the different myelin membrane components at distinct spatial localization, possibly to prevent premature and inappropriate assembly. It is therefore possible that the regulation of myelin membrane trafficking is one important mechanism that induces myelin membrane assembly at the appropriate time during development. Indeed, previous work has provided evidence that the trafficking of PLP is influenced by neurons (16Kippert A. Trajkovic K. Rajendran L. Ries J. Simons M. J. Neurosci. 2007; 27: 3560-3570Crossref PubMed Scopus (48) Google Scholar, 17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). A relatively large fraction of PLP is delivered to late endosomes/lysosomes in cultured oligodendrocytes, whereas the localization of PLP to late endosomes/lysosomes is reduced after coculture with neurons (17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). These late endosomal multivesicular bodies (MVBs) can either be the endosomal for or they can with the membrane to vesicles into the extracellular space and are then exosomes M. G. Curr. Opin Cell Biol. 2009; 21: PubMed Scopus Google Scholar, C. M. Nat. Rev. 2009; PubMed Google Scholar). are membrane vesicles with a of that are into the extracellular space by many different they an important in processes such as protein of of and C. M. Nat. Rev. 2009; PubMed Google Scholar, A. Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). have that oligodendrocytes secrete relatively large amounts of but the of these vesicles has N. S. C. W. H. Nave K.A. H. Trotter J. 2007; Scopus Google Scholar, K. C. S. Rajendran L. Wenzel D. F. P. B. Simons M. PubMed Scopus Google Scholar). Here, we the of exosomes in cell have that a relatively large fraction of PLP is in oligodendrocytes within late endosomes/lysosomes (17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). the localization of PLP in in an of of different was PLP was in the cell of oligodendrocytes with at and to an at was a of PLP within the cell a as PLP and These show that the of endosomal localization of these myelin membrane proteins is on the of oligodendrocytes. that intracellular of PLP and premyelinating oligodendrocytes that have not yet myelin these oligodendrocytes in is we of that myelin basic Indeed, we a number of oligodendrocytes and within the cell at of from A and that the cell bodies to oligodendrocytes as a we that the cells were not and after not is not oligodendrocytes myelin membrane proteins in late endosomes/lysosomes to is that oligodendrocytes myelin in is to for is that late or are part of a system that the process of myelin membrane In fact, we and N. S. C. W. H. Nave K.A. H. Trotter J. 2007; Scopus Google Scholar, C. Y. S. N. Jung S. M.A. M. M. W. J. Simons M. J. Cell Biol. 2010; PubMed Scopus Google have that cells secrete exosomes that are to be within and after the of the with the a process regulated by intracellular have that oligodendrocytes to neuronal by intracellular B. S. V. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar). These exosomes are therefore with a possible in myelin membrane formation. the possible of exosomes in we an from conditioned of of oligodendrocytes. with to a small membrane vesicles with a of to and of exosome-like vesicles from of oligodendrocytes. the of cultured for was and to and as The of were by for cell and were by for the the was and with of PLP in the the the membrane fraction amounts of and whereas and Nogo A were coculture system was used to the possible of exosomes in CNS were from oligodendrocytes and to a coculture at in was and were used to as B. S. V. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar, Chan C. J. Neurosci. 2009; PubMed Scopus Google Scholar). we found that exosome-like vesicles these results to a of these vesicles in we secretion was influenced by neuronal We have that the treatment of cells with conditioned from conditioned the late of PLP (17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). the of on the of oligodendrocytes was by after in and secretion was by determining the amount of PLP of oligodendrocytes with to a of PLP conditioned reduced the secretion of and was not we not this is to distinct processes into the or separate of vesicles inhibit oligodendrocytes and neurons were after coculture with exosomes for The cells were for and myelinating oligodendrocytes were by determining the number of cells with processes and as the of cells cells from conditioned and from oligodendrocytes. oligodendrocytes were cultured for to and exosome-like vesicles from the by the amount of and was in the cell and in the fraction the in exosomes we the of exosome-like vesicles on cultured oligodendrocytes. First, we exosomes oligodendrocyte by a on changes in was in oligodendrocytes when with the and the cell were not not we the possible effects of exosome-like vesicles on oligodendrocytes by a B.A. J.T. W.D. Raff M.C. Cell. Full Text PDF PubMed Scopus Google Scholar). of cell was not by the treatment with exosome-like vesicles We the of exosomes in oligodendrocyte oligodendrocytes were cultured in or in and we that oligodendrocyte differentiation as by an in the fraction of of oligodendrocytes with exosome-like vesicles not this we in these an of exosome-like vesicles on cell treatment in a relatively in the of oligodendrocytes as with cells in control medium. This was in both and cells of cells with exosome-like vesicles the of on cell vesicles cell of oligodendrocytes. oligodendrocytes were with after in and the was after of oligodendrocytes were in or of of oligodendrocytes with exosome-like vesicles not prevent oligodendrocyte cell from treatment of oligodendrocytes with for the number of of with exosome-like vesicles not the number of cells from and oligodendrocytes were for with and incubated with exosome-like vesicles during the as Cell of and cells was as under with in an in cell of exosome-like vesicles prevented the in cell from of not a of exosome-like vesicles in cell we the in this The is to the myelin membrane formation in oligodendrocytes N. P. M. J. Neurosci. 2009; PubMed Scopus Google Scholar, S.P. F. Macklin J. Neurosci. 2009; PubMed Scopus Google Scholar, S.P. E.N. X. G. R.L. Macklin J. Neurosci. PubMed Scopus Google Scholar). of results in the of and the exosome-like vesicles not the of these proteins when with control this a in the changes in cell previous have a for the in oligodendrocyte branching and cell S. Miller R.H. Lee X. Scott M.L. Shulag-Morskaya S. Shao Z. Chang J. Thill G. Levesque M. Zhang M. Hession C. Sah D. Trapp B. He Z. Jung V. McCoy J.M. Pepinsky R.B. Nat. Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (504) Google Scholar, A. Trajkovic K. Rajendran L. Ries J. Simons M. J. Neurosci. 2007; 27: 3560-3570Crossref PubMed Scopus (48) Google Scholar, X. J. Neurosci. PubMed Scopus Google Scholar, A. D. J. Simons M. Cell Biol. 2009; PubMed Scopus Google Scholar). we the that exosome-like vesicles by Indeed, when we used the inhibitory of exosome-like vesicles on cell was results were when the was used in the Importantly, we found that both and not cell of oligodendrocytes cultured in in the of exosome-like vesicles A and these that exosome-like vesicles the to prevent cell of oligodendrocytes. the of its was by of from cell the of A that the of is treatment of oligodendrocytes with exosome-like vesicles for this the of a molecule of was We found that when cells were with exosome-like vesicles these that exosome-like vesicles by actomyosin in of actomyosin the effects of exosome-like vesicles on cell oligodendrocytes were for with and incubated with exosome-like vesicles during the in the or of The cells were for and not cell of and cells with only but the inhibitory of exosomes on cell was reduced by with from oligodendrocytes were cultured in for with or exosome-like a the amount of with was with to an in as with the control the of was after treatment of oligodendrocytes with exosome-like vesicles not cell of and cells with only but the inhibitory of exosomes on cell was reduced by from with is to in oligodendrocytes X. J. Neurosci. PubMed Scopus Google Scholar). have that a of an important in CNS by morphological differentiation of oligodendrocytes Chan C. J. Neurosci. 2009; PubMed Scopus Google Scholar, J. J. Biol. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, J. W. S. H. J. Neurosci. 2009; PubMed Scopus Google Scholar, R. C. N. S. Trotter J. J. Cell Biol. PubMed Scopus Google Scholar, J. T. T. H. T. Cell Neurosci. PubMed Scopus (44) Google Scholar, A. J. Cell Biol. PubMed Scopus Google Scholar, H. S. T. S. T. 1994; PubMed Scopus Google Scholar). We used the small molecular to oligodendrocytes cell in a of cultured oligodendrocytes with the cell by A and are regulated by the of an in and in and by an inhibitory in and in in the we the of and after a in the but not the in cells that incubated with exosomes and is to the has to CNS A.D. R.J. B. J. Neurosci. 2009; PubMed Scopus Google Scholar, J. Z. C. M. D.L. Brophy P.J. A. C. J. Cell Biol. 2009; PubMed Scopus Google Scholar). and various extracellular signals in to at a for the of such as We the of in and a in after treatment and vesicles oligodendrocytes were cultured for in in the or of for the The cells were for and B. of cells with to a in cell of and not cell of oligodendrocytes cultured in the of from different with oligodendrocytes were for with and either incubated with exosome-like vesicles during the or Cell were by for for major in and for as a the of is the of was for of is as the from not we have that oligodendrocyte secrete exosome-like vesicles that seem to have an autoinhibitory by oligodendrocyte we that one or factors in neuronal conditioned inhibit the of exosome-like vesicles from oligodendrocytes. on these we propose a in neurons control differentiation of oligodendrocytes by the secretion of autoinhibitory exosomes from not seem to the differentiation of oligodendrocytes from but to control the properties of the the factors that have to the of oligodendrocytes, many of the of proliferating, immature OPCs into oligodendrocytes (1Chong S.Y. Chan J.R. J. Cell Biol. 2010; 188: 305-312Crossref PubMed Scopus (44) Google Scholar). many of the factors are on axons and seem to inhibit the differentiation of OPCs polysialylated neural cell adhesion molecule on axons during development or the OPC differentiation (9Wang S. Sdrulla A.D. diSibio G. Bush G. Nofziger D. Hicks C. Weinmaster G. Barres B.A. Neuron. 1998; 21: 63-75Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 10Charles P. Hernandez M.P. Stankoff B. Aigrot M.S. Colin C. Rougon G. Zalc B. Lubetzki C. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 7585-7590Crossref PubMed Scopus (241) Google Scholar, 12Zhang Y. Argaw A.T. Gurfein B.T. Zameer A. Snyder B.J. Ge C. Lu Q.R. Rowitch D.H. Raine C.S. Brosnan C.F. John G.R. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 19162-19167Crossref PubMed Scopus (158) Google Scholar). that OPC differentiation are the LINGO-1 and secretion S. Miller R.H. Lee X. Scott M.L. Shulag-Morskaya S. Shao Z. Chang J. Thill G. Levesque M. Zhang M. Hession C. Sah D. Trapp B. He Z. Jung V. McCoy J.M. Pepinsky R.B. Nat. Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (504) Google Scholar, 12Zhang Y. Argaw A.T. Gurfein B.T. Zameer A. Snyder B.J. Ge C. Lu Q.R. Rowitch D.H. Raine C.S. Brosnan C.F. John G.R. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 19162-19167Crossref PubMed Scopus (158) Google Scholar, 14Ye F. Chen Y. Hoang T. Montgomery R.L. Zhao X.H. Bu H. Hu T. Taketo M.M. van Es J.H. Clevers H. Hsieh J. Bassel-Duby R. Olson E.N. Lu Q.R. Nat. Neurosci. 2009; 12: 829-838Crossref PubMed Scopus (450) Google Scholar, C. S. K. T. D. H. M. A. B. Nat. Neurosci. 2009; 12: PubMed Scopus Google Scholar). In the of these and be for the differentiation that results in R.J. C. Nat. Rev. Neurosci. PubMed Scopus Google premyelinating oligodendrocytes have in that extend processes for myelin proteins A. R. Trapp B.D. N. J. PubMed Scopus Google Scholar). These cells have in differentiating from OPCs but have to possibly they are not receiving the appropriate signals from the oligodendrocytes are not found in the but for a relatively short time during the development of the CNS (15Trapp B.D. Nishiyama A. Cheng D. Macklin W. J. Cell Biol. 1997; 137: 459-468Crossref PubMed Scopus (305) Google is likely that the oligodendrocytes with and within cell bodies in our premyelinating oligodendrocytes. We that localization of PLP to late endosomes/lysosomes at and is at It is to that these the in exosomes are It is possible that at of oligodendrocyte neuronal signals the generation of and the of new is that exosomes are at the membrane by of vesicles into the extracellular the premyelinating oligodendrocytes that have in large for the proteolipid protein A. R. Trapp B.D. N. J. PubMed Scopus Google Scholar). It be to PLP in late endosomes/lysosomes and is in with exosomes in these premyelinating oligodendrocytes in signals for the regulation of secretion are but they to changes in intracellular that are to N. S. C. W. H. Nave K.A. H. Trotter J. 2007; Scopus Google Scholar). It is to the effects of exosomes to myelin by Myelin a inhibitory on OPC differentiation they are from the extracellular space by Zhao C. Franklin R.J. J. Neurosci. 2006; PubMed Scopus Google Scholar, A. N. Franklin R.J. 2001; PubMed Scopus Google Scholar, R.H. Dev. Biol. PubMed Scopus Google Scholar). of myelin in of results in of by oligodendrocyte differentiation in a premyelinating Zhao C. Franklin R.J. J. Neurosci. 2006; PubMed Scopus Google Scholar). evidence has provided that the inhibitory on OPC differentiation by myelin is by A.S. D. R. C. Franklin R.J. F. G. 2009; PubMed Scopus Google Scholar). These results show that myelin membrane components present within myelin and in exosomes processes by a is that the myelin membrane proteins are and protein this LINGO-1 is molecule that the and and S. Miller R.H. Lee X. Scott M.L. Shulag-Morskaya S. Shao Z. Chang J. Thill G. Levesque M. Zhang M. Hession C. Sah D. Trapp B. He Z. Jung V. McCoy J.M. Pepinsky R.B. Nat. Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (504) Google Scholar). In has to oligodendrocyte process branching and membrane and S. K.A. Development. 2009; PubMed Scopus Google is not are many inhibitory cues to myelin membrane formation in the CNS, whereas many factors have to control by cells in the nervous The complex of the of to different myelin on separate axons by one oligodendrocyte is likely to be one The of inhibitory cues from the microenvironment of oligodendrocytes initiate formation of process at the conclusion, our results provide new evidence for small and diffusible oligodendroglial-derived vesicular carriers within the extracellular space that have inhibitory properties on cellular growth. We propose that secretion of these exosomes coordinate myelin membrane biogenesis. IntroductionDuring the development of the CNS, oligodendrocyte precursor cells (OPCs) 2The abbreviations used are: OPColigodendrocyte precursor cellPLPproteolipid proteinPpostnatal dayMBPmyelin basic proteinMVBmultivesicular bodyNCMneuronal conditioned mediumCNPase2′,3′-cyclic nucleotide 3′-phosphodiesteraseMAGmyelin-associated glycoproteinMOGmyelin oligodendrocyte glycoprotein. undergo major changes in cell morphology when they start to differentiate into myelin-forming oligodendrocytes (1Chong S.Y. Chan J.R. J. Cell Biol. 2010; 188: 305-312Crossref PubMed Scopus (44) Google Scholar, 2Richardson W.D. Kessaris N. Pringle N. Nat. Rev. Neurosci. 2006; 7: 11-18Crossref PubMed Scopus (303) Google Scholar, 3Baumann N. Pham-Dinh D. Physiol. Rev. 2001; 81: 871-927Crossref PubMed Scopus (1320) Google Scholar). First, a large network of branching processes is formed, and then oligodendrocytes start to extend massive amounts of myelin membrane sheaths (4Simons M. Trotter J. Curr. Opin Neurobiol. 2007; 17: 533-540Crossref PubMed Scopus (164) Google Scholar, 5Sherman D.L. Brophy P.J. Nat. Rev. Neurosci. 2005; 6: 683-690Crossref PubMed Scopus (485) Google Scholar). The generation of myelinating oligodendrocytes from proliferating, immature OPCs is complex and depends on an intrinsic genetic differentiation program that is regulated in part by an intracellular molecular clock determining how many times an OPC can divide before differentiating (6Temple S. Raff M.C. Cell. 1986; 44: 773-779Abstract Full Text PDF PubMed Scopus (361) Google Scholar, 7Barres B.A. Lazar M.A. Raff M.C. Development. 1994; 120: 1097-1108Crossref PubMed Google Scholar, 8Dugas J.C. Ibrahim A. Barres B.A. J. Neurosci. 2007; 27: 6185-6196Crossref PubMed Scopus (66) Google Scholar). This intrinsic program is under the control of various extrinsic factors present within the microenvironment of oligodendrocytes. Many of these factors such as Notch1, Wnt, LINGO-1 (leucine-rich repeat, and Ig domain-containing, Nogo receptor-interacting protein 1), or the polysialylated neural cell adhesion molecule are inhibitory in nature and prevent OPCs from differentiating into mature oligodendrocytes (9Wang S. Sdrulla A.D. diSibio G. Bush G. Nofziger D. Hicks C. Weinmaster G. Barres B.A. Neuron. 1998; 21: 63-75Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 10Charles P. Hernandez M.P. Stankoff B. Aigrot M.S. Colin C. Rougon G. Zalc B. Lubetzki C. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 7585-7590Crossref PubMed Scopus (241) Google Scholar, 11Mi S. Miller R.H. Lee X. Scott M.L. Shulag-Morskaya S. Shao Z. Chang J. Thill G. Levesque M. Zhang M. Hession C. Sah D. Trapp B. He Z. Jung V. McCoy J.M. Pepinsky R.B. Nat. Neurosci. 2005; 8: 745-751Crossref PubMed Scopus (504) Google Scholar, 12Zhang Y. Argaw A.T. Gurfein B.T. Zameer A. Snyder B.J. Ge C. Lu Q.R. Rowitch D.H. Raine C.S. Brosnan C.F. John G.R. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 19162-19167Crossref PubMed Scopus (158) Google Scholar, 13Fancy S.P. Baranzini S.E. Zhao C. Yuk D.I. Irvine K.A. Kaing S. Sanai N. Franklin R.J. Rowitch D.H. Genes Dev. 2009; 23: 1571-1585Crossref PubMed Scopus (463) Google Scholar, 14Ye F. Chen Y. Hoang T. Montgomery R.L. Zhao X.H. Bu H. Hu T. Taketo M.M. van Es J.H. Clevers H. Hsieh J. Bassel-Duby R. Olson E.N. Lu Q.R. Nat. Neurosci. 2009; 12: 829-838Crossref PubMed Scopus (450) Google Scholar). Down-regulation of these inhibitory cues seems to be an important mechanism in triggering the differentiation of oligodendrocytes. Once differentiation of oligodendrocytes is induced, the cells start to synthesize large amount of myelin membrane components including lipids and several myelin-specific proteins, the major ones of these being the proteolipid protein (PLP) and the myelin basic proteins (MBP). Curiously, the biosynthesis of the major myelin membrane components occurs before the assembly of myelin is initiated, most likely by neuronal factor(s). In fact, such premyelinating oligodendrocytes that have started to synthesize myelin lipids and proteins but have not yet wrapped myelin around axons are only found for a relatively short period during the development of the CNS (15Trapp B.D. Nishiyama A. Cheng D. Macklin W. J. Cell Biol. 1997; 137: 459-468Crossref PubMed Scopus (305) Google Scholar). Importantly, these premyelinating oligodendrocytes seem to separate the different myelin membrane components at distinct spatial localization, possibly to prevent premature and inappropriate assembly. It is therefore possible that the regulation of myelin membrane trafficking is one important mechanism that induces myelin membrane assembly at the appropriate time during development. Indeed, previous work has provided evidence that the trafficking of PLP is influenced by neurons (16Kippert A. Trajkovic K. Rajendran L. Ries J. Simons M. J. Neurosci. 2007; 27: 3560-3570Crossref PubMed Scopus (48) Google Scholar, 17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). A relatively large fraction of PLP is delivered to late endosomes/lysosomes in cultured oligodendrocytes, whereas the localization of PLP to late endosomes/lysosomes is reduced after coculture with neurons (17Trajkovic K. Dhaunchak A.S. Goncalves J.T. Wenzel D. Schneider A. Bunt G. Nave K.A. Simons M. J. Cell Biol. 2006; 172: 937-948Crossref PubMed Scopus (134) Google Scholar). These late endosomal multivesicular bodies (MVBs) can either be the endosomal for or they can with the membrane to vesicles into the extracellular space and are then exosomes M. G. Curr. Opin Cell Biol. 2009; 21: PubMed Scopus Google Scholar, C. M. Nat. Rev. 2009; PubMed Google Scholar). are membrane vesicles with a of that are into the extracellular space by many different they an important in processes such as protein of of and C. M. Nat. Rev. 2009; PubMed Google Scholar, A. Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). have that oligodendrocytes secrete relatively large amounts of but the of these vesicles has N. S. C. W. H. Nave K.A. H. Trotter J. 2007; Scopus Google Scholar, K. C. S. Rajendran L. Wenzel D. F. P. B. Simons M. PubMed Scopus Google Scholar). Here, we the of exosomes in cell
Bakhti et al. (Wed,) studied this question.