Myelin Biogenesis: Sorting out Protein Trafficking

Myelin Biogenesis: Sorting out Protein Trafficking

Current Biology Vol 16 No 11 R418 HeLa cells. J. Biol. Chem. 278, 45160–45170. 18. Michaely, P., Li, W.P., Anderson, R.G., Cohen, J.C., and Hobbs, H...

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Current Biology Vol 16 No 11 R418

HeLa cells. J. Biol. Chem. 278, 45160–45170. 18. Michaely, P., Li, W.P., Anderson, R.G., Cohen, J.C., and Hobbs, H.H. (2004). The modular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in

coated pits. J. Biol. Chem. 279, 34023–34031. 19. White, I.J., Bailey, L.M., Aghakhani, M.R., Moss, S.E., and Futter, C.E. (2006). EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation. EMBO J. 25, 1–12.

Myelin Biogenesis: Sorting out Protein Trafficking Myelin biogenesis is a complex process involving coordinated exocytosis, endocytosis, mRNA transport and cytoskeletal dynamics. Recent studies indicate that soluble neuronal signals may control the surface expression of proteolipid protein, a process that involves reduced endocytosis and/or increased transport carrier recruitment from an intracellular pool. Mihaela Anitei and Steven E. Pfeiffer Myelin is a dynamic, multilamellar membrane which ensheathes axons, providing the structural basis for saltatory nerve conduction which allows for increases in the speed of action potential propagation and dramatic savings in both energy consumption and space requirements; without myelin, neurons would have to have significantly larger diameters to achieve the same conduction speed [1–3]. The myelin sheath also participates in bidirectional communication with both its partner axons and the environment [1–3]. For example, myelin regulates axon diameter and is a key player in ion channel clustering at nodes of Ranvier [4]. Myelin-associated glycoprotein can inhibit neurite outgrowth during axonal regeneration; reciprocally, neurons regulate myelin gene expression, oligodendrocyte survival [1] and, as recently reported by Trajkovic et al. [5], myelin proteolipid protein recruitment to the membrane. Loss or damage of myelin results in serious neurological disorders such as multiple sclerosis [1]. Remyelination is limited to a few lamellae, restoration of function is generally poor, and therapies remain suboptimal. The interdependence of myelin and axons takes on increasing

importance with recognition of axonal degeneration in demyelinating disease. Myelin biogenesis is a major part of brain development. As oligodendrocytes enter terminal differentiation, coordinated myelin gene expression is initiated, oligodendrocyte processes interact with axons, and myelin is produced as a specialization of the oligodendrocyte plasma membranes on a remarkable scale of approximately 5–50 x 103 mm2 membrane per cell per day [2,3]. Although myelin-like membranes are synthesized in culture without neuronal contact, in vivo the quantity and stability of myelin is strongly enhanced by oligodendrocyte–neuron interactions [2,3]. While myelin has a relatively simple pattern of major proteins, there are myriad quantitatively, though certainly not functionally, ‘minor’ proteins [6], some of which have been implicated in demyelinating diseases [7]. Further, myelin has multiple domains: myelin basic protein and proteolipid protein are found abundantly in compact internodal myelin; oligodendrocyte specific protein is localized to junctions that spiral through the myelin sheath; neurofascin-155 is concentrated at paranodes; and myelin-associated glycoprotein and myelin oligodendrocyte protein are concentrated in periaxonal and outer lamellae, respectively [2,4].

Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. E-mail: [email protected] DOI: 10.1016/j.cub.2006.05.009

This asymmetric distribution of proteins provides myelin with the potential for functional diversity and compartmentalization of activity. However, with the long distances myelin membrane components may need to travel along oligodendrocyte processes to reach their target membranes, this also imposes additional burdens on the biosynthetic and trafficking mechanisms. One would therefore expect that molecules that regulate and coordinate the trafficking and recruitment of transport carriers to the plasma membrane and cytoskeletal dynamics would be essential for oligodendrocyte differentiation and myelin biogenesis. For example, mRNA molecules encoding myelin basic protein are transported to compact myelin in granules that contain specific components of the translation and transport machineries [2]. Exocytic transport regulators, such as Rab3a, the exocyst components Sec8 and Sec6, and the exocyst regulator RalA, are expressed at high levels in myelin; Rab3a and the v-SNARE synaptobrevin-2 are up-regulated during maturation of oligodendrocytes; and Sec8 is central for oligodendrocyte process growth and arborization [2,8,9]. A recent genetic screen in zebrafish [10] showed that N-ethylmaleimide sensitive factor, a protein critical for membrane fusion, is required for correct expression of myelin basic protein and formation of nodes of Ranvier. Current hypotheses suggest that recycling endosomes play central roles in protein sorting and trafficking, both during plasma membrane recycling and as an intermediate step during cargo transport from the trans-Golgi network to the plasma membrane [11] (Figure 1). Trajkovic et al. [5] investigated how axonal signals might control myelin biogenesis,

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Neuron Extracellular matrix



Neuronal soluble signal(s) Adhesion molecule

Integrin complex

Integrin complex


Oligodendrocyte plasma membrane



Rab effector cAMP/PKA

E Exocytic carrier



RhoA, cdc42, Rac

D Actin Endocytic vesicle


B C Microtubule Recycling endosome

Trans-Golgi network

Myelin protein (e.g., PLP) The exocyst tethering complex Multidomain scaffolding proteins Molecular motor

Rab Ral Small GTPase (unidentified)


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Figure 1. A model for the regulation of myelin protein trafficking. Soluble signals derived from neurons activate receptors on the surface of oligodendrocytes, such as G-protein-coupled receptors (GPCR) which activate adenylate cyclase (AC), stimulating cAMP synthesis and leading to PKA activation. The activation of intracellular signaling pathways, such as cAMP/PKA: (A) decreases membrane recycling; (B,C) enhances vesicle recruitment from (B) recycling endosomes and/or (C) the exocytic compartment; (D) modulates cytoskeleton dynamics via Rho GTPases; and/or (E) augments vesicle docking, for example via Rab activation. (F) Neurons may also signal via surface adhesion molecules. (G) Integrins on the oligodendrocyte membrane modulate cytoskeleton dynamics via Rho GTPases, and the recruitment of trafficking carriers to the membrane via transport regulators, such as Rab, Ral and the exocyst.

obtaining results that suggest that late endosomes/lysosomes may contribute to this process. For this, they used first primary oligodendrocytes, and then, more extensively, two cell lines with some of the characteristics of oligodendrocytes. They concentrated on the major myelin protein proteolipid protein, the biosynthesis and transport of which coincide with the induction of myelination [12]. It is noteworthy

that perturbations in the transport and or degradation pathways for protein proteolipid are associated with major myelin pathologies [1]. Taking advantage of the fact that, in one of the cell lines (Olineu), proteolipid protein is normally detected at minimal levels on the plasma membrane, Trajkovic et al. [5] showed that the amount of proteolipid protein on the cell surface increased in the presence of neurons or neuron-conditioned

medium. This could in principle be due to reduced proteolipid protein endocytosis and/or increased proteolipid protein trafficking to the cell surface. Using another cell line (OLN-93) that does express proteolipid protein on the surface, they showed that neuronal signals reduced the internalization of surface proteolipid protein in a clathrinindependent process that involved the actin cytoskeleton and RhoA,

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a small GTPase known to couple the actin cytoskeleton to membrane dynamics [13]. In both cell lines, as well as in primary oligodendrocytes, a portion of proteolipid protein was present in a LAMP1-positive late endosome/lysosome compartment. In primary oligodendrocytes, overall endocytosis was also reduced in the presence of neurons, whereas the half-life of proteolipid protein was not changed. Quantitative analysis is needed to clarify the effect neuronal signals have on endocytosis and exocytosis in oligodendrocytes and the amount of proteolipid protein present in the post-Golgi exocytic compared to the endosomal compartment in primary oligodendrocytes both in vivo and in vitro (for example, we find that only about 40–50% of proteolipid protein is co-localized with LAMP-1 in primary oligodendrocytes even in the absence of neurons). To determine whether neuronal signaling also increases proteolipid protein transport to the membrane, Trajkovic et al. [5] analyzed the motility of a proteolipid protein– EGFP fluorescent fusion protein and late endosome/lysosome carriers labeled with the marker lysotracker in the Oli-neu cell line. In the absence of neurons, they found that particle motility was, perhaps surprisingly, minimal; in the presence of neurons, carrier motility was increased to approximately 29% of total particles, a level of activity similar to that normally observed in primary oligodendrocytes cultured without neurons (our unpublished data). In addition, in the presence of neurons, the fusion of lysotracker-positive carriers with the Oli-neu cell membrane was also elevated. This indicates that neuronal signal(s) increase the transport and recruitment of late endosome/lysosome carriers to the plasma membrane. There are, however, some reasons for caution in this interpretation. The fact that proteolipid protein is present at reduced levels on the surface in Oli-neu cells compared to primary oligodendrocytes suggests that Oli-neu cells may lack part of the

machinery involved in exocytic proteolipid protein transport, or that they recycle proteolipid protein much more rapidly than primary oligodendrocytes. Quantifications of anterograde and retrograde carrier movement and membrane fusion events in primary oligodendrocytes compared to Oli-neu/OLN-93 cells would be important in order to address this. Optimization of methods that allow combined genetic and time-lapse microscopy analyses of myelination, in particular primary oligodendrocytes co-cultured with neurons [14], or in vivo studies in zebrafish [10], should contribute to a better understanding of these phenomena. An additional interesting finding in this study is that soluble neuronal signals are sufficient for stimulating proteolipid protein insertion into the membrane. Effects of pharmacological inhibitors suggest that cyclic AMP (cAMP) and protein kinase A (PKA) have a role in proteolipid protein trafficking, consistent with previous data showing that cAMP stimulation increases oligodendrocyte differentiation [15]. However, as cAMP alone stimulates proteolipid protein surface expression relatively modestly, compared to neuronconditioned medium, other molecules, as well as direct oligodendrocyte-neuron interactions, are likely to contribute to the polarized organization of the myelin membrane. The new study of Trajkovic et al. [5] provides further evidence that myelin biogenesis responds to neuronal signals, and indicates that at least a portion of proteolipid protein trafficking could occur via endosomes. Incorporating these findings, we propose a general model in which neurons, via soluble signals (Figure 1A–E) and/or surface adhesion molecules (Figure 1F,G), activate oligodendrocyte intracellular signaling pathways, such as cAMP/ PKA, leading to a decrease in membrane recycling (Figure 1A), and/or increase in the recruitment of transport carriers from either an endosomal (Figure 1B) or an exocytic compartment (Figure 1C) [11,16,17]. This may involve

modulation of carrier motility via molecular motor activation and cytoskeletal remodeling (Figure 1D); vesicle docking, for example by favoring interactions between Rabs and Rab effectors (Figure 1E); and/or SNAREmediated fusion. Additionally, extracellular signals transmitted via integrins (Figure 1G) may regulate cytoskeleton dynamics via RhoGTPases and Fyn [18,19], and the recruitment of trafficking carriers to the membrane via transport proteins such as Rab, RalA and the exocyst [9,20]. Future studies are expected to confirm and characterize the molecular players involved in these processes. References 1. Lazzarini, R.A. (2004). Myelin and its Diseases (New York: Academic Press). 2. Trapp, B.D., Pfeiffer, S.E., Anitei, M., and Kidd, G.J. (2004). Cell biology of myelin assembly. In Myelin and its Diseases, Lazzarinni., ed. (New York: Academic Press), pp. 29–48. 3. Pfeiffer, S.E., Warrington, A.E., and Bansal, R. (1993). The oligodendrocyte and its many cellular processes. Trends Cell. Biol. 3, 191–197. 4. Salzer, J.L. (2003). Polarized domains of myelinated axons. Neuron 40, 297–318. 5. Trajkovic, K., Dhaunchak, A.S., Goncalves, J.T., Wenzel, D., Schneider, A., Bunt, G., Nave, K.A., and Simons, M. (2006). Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J. Cell Biol. 172, 937–948. 6. Taylor, C.M., Marta, C.B., Claycomb, R.J., Han, D.K., Rasband, M.N., Coetzee, T., and Pfeiffer, S.E. (2004). Proteomic mapping provides powerful insights into functional myelin biology. Proc. Natl. Acad. Sci. USA 101, 4643–4648. 7. Marta, C.B., Oliver, A.R., Sweet, R.A., Pfeiffer, S.E., and Ruddle, N.H. (2005). Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology. Proc. Natl. Acad. Sci. USA 102, 13992–13997. 8. Madison, D.L., Krueger, W.H., Cheng, D., Trapp, B.D., and Pfeiffer, S.E. (1999). SNARE complex proteins, including the cognate pair VAMP-2 and syntaxin-4, are expressed in cultured oligodendrocytes. J. Neurochem 72, 988–998. 9. Anitei, M., Ifrim, M., Ewart, M.A., Cowan, A.E., Carson, J.H., Bansal, R., and Pfeiffer, S.E. (2006). A role for Sec8 in oligodendrocyte morphological differentiation. J. Cell Sci. 119, 807–818. 10. Woods, I.G., Lyons, D.A., Voas, M.G., Pogoda, H.M., and Talbot, W.S. (2006). NSF is essential for organization of myelinated axons in zebrafish. Curr. Biol. 16, 636–648. 11. Ang, A.L., Taguchi, T., Francis, S., Folsch, H., Murrells, L.J., Pypaert, M., Warren, G., and Mellman, I. (2004). Recycling endosomes can serve as intermediates during transport from the Golgi to the plasma membrane of MDCK cells. J. Cell Biol. 167, 531–543. 12. Trapp, B.D., Nishiyama, A., Cheng, D., and Macklin, W. (1997). Differentiation and death of premyelinating oligodendrocytes

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in developing rodent brain. J. Cell Biol. 137, 459–468. 13. Bader, M.F., Doussau, F., ChasserotGolaz, S., Vitale, N., and Gasman, S. (2004). Coupling actin and membrane dynamics during calcium-regulated exocytosis: a role for Rho and ARF GTPases. Biochim. Biophys. Acta 1742, 37–49. 14. Chan, J.R., Watkins, T.A., Cosgaya, J.M., Zhang, C., Chen, L., Reichardt, L.F., Shooter, E.M., and Barres, B.A. (2004). NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43, 183–191. 15. McMorris, F.A. (1983). Cyclic AMP induction of the myelin enzyme 2’,





3’-cyclic nucleotide 3’-phosphohydrolase in rat oligodendrocytes. J. Neurochem. 41, 506–515. Seino, S., and Shibasaki, T. (2005). PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol. Rev. 85, 1303–1342. Jahn, R. (2004). Principles of exocytosis and membrane fusion. Ann. N.Y. Acad. Sci. 1014, 170–178. Liang, X., Draghi, N.A., and Resh, M.D. (2004). Signaling from integrins to Fyn to Rho family GTPases regulates morphologic differentiation of oligodendrocytes. J. Neurosci 24, 7140–7149. Colognato, H., Ramachandrappa, S., Olsen, I.M., and ffrench-Constant, C.

Cognition and Evolution: Learning and the Evolution of Sex Traits The evolution of gender characteristics is an outcome of mate choice, which has been assumed to be genetically mediated. Recent research suggests that learning also has a role to play as an agent of sexual selection. Spencer K. Lynn Many animals, some birds being well known examples, exhibit conspicuous appearance (e.g., bright, colorful plumage or extravagant tails) at some cost (e.g., attracting predators). Models for the evolution of such traits have posited strong genetic links between expression of the trait, e.g., by males, and preference for the trait, e.g., by females exercising mate choice. The traits are considered to be indicators of Darwinian fitness and the preferences are thought to be unlearned [1]. Sexual imprinting, exhibited by many animals, including humans [2], is one exception. Imprinting refers to a form of learning confined to a sensitive period at the beginning of an animal’s life. Preferences are established by exposure to parental traits shortly after birth. Those preferences show later, in the young adult, when the animal makes choices about whom to court. On the surface, however, imprinting alone was not thought to drive a preference for traits different from those expressed by the parents. Instead, some form of inflexible perceptual bias was thought to be required to drive

selection for exaggeration of imprinted traits [3–6]. However, recent research indicates that an outcome of discrimination learning, known as ‘peak shift’, may couple learning to

* S+

(2004). Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. J. Cell Biol. 167, 365–375. 20. Lalli, G., and Hall, A. (2005). Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex. J. Cell Biol. 171, 857–869.

Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030, USA. E-mail: [email protected]

DOI: 10.1016/j.cub.2006.05.010

the evolution of trait exaggeration. Peak shift is a behavioral phenomenon arising from discrimination learning and has become one of several topics in psychology taken up by behavioral ecologists seeking to bridge learning and decision-making to the evolution of cognitive abilities. In particular, peak shift has been implicated in the evolution of signaling systems. Theoretical studies have explored the potential role of peak shift in the evolution of gender or species recognition characters, warning coloration and


Generalization to females Generalization to males Utility Current Biology

Figure 1. Peak shift is a directional preference for novel stimuli characterized by aversion to the risk of stimulus misidentification. In this illustration, after the experiment by ten Cate et al. [13], male zebra finch chicks learn what adult males and females look like by imprinting on their parents (S+, maternal beak color, and S2, paternal beak color). Later, as young adult birds, the males are allowed a choice of females to court (eight beak colors). The males generalize what they have learned about their parental beak colors to similar beak colors (bell-shaped generalization curves). When these generalizations overlap, uncertainty ensues about the outcome of responding to stimuli: any given beak color might indicate a male or a female. How should a young bird decide who to court? Response strength (e.g., amount of courtship behavior) can be described by a utility function (Box 1). The utility function exhibits peak shift, predicting that a bird with a somewhat redder beak than the mother (asterisk) will be courted more vigorously than one with the mother’s beak color, as shown by the ten Cate et al. experiment [13].