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Title: A Role for Myosin VI in the Localization of Axonal Proteins}
Article:
Abstract:
In neurons polarized trafficking of vesicle-bound membrane proteins gives rise to the distinct molecular composition and functional properties of axons and dendrites. Despite their central role in shaping neuronal form and function, surprisingly little is known about the molecular processes that mediate polarized targeting of neuronal proteins. Recently, the plus-end-directed motor Myosin Va was shown to play a critical role in targeting of transmembrane proteins to dendrites; however, the role of myosin motors in axonal targeting is unknown. Here we show that Myosin VI, a minus-end-directed motor, plays a vital role in the enrichment of proteins on the surface of axons. Engineering non-neuronal proteins to interact with Myosin VI causes them to become highly concentrated at the axonal surface in dissociated rat cortical neurons. Furthermore, disruption of either Myosin VI function or expression leads to aberrant dendritic localization of axonal proteins. Myosin VI mediates the enrichment of proteins on the axonal surface at least in part by stimulating dendrite-specific endocytosis, a mechanism that has been shown to underlie the localization of many axonal proteins. In addition, a version of Channelrhodopsin 2 that was engineered to bind to Myosin VI is concentrated at the surface of the axon of cortical neurons in mice in vivo, suggesting that it could be a useful tool for probing circuit structure and function. Together, our results indicate that myosins help shape the polarized distributions of both axonal and dendritic proteins.
Introduction:
Following synthesis in the secretory pathway, axonal and dendritic transmembrane proteins follow distinct transport pathways to the plasma membrane. After being sorted into separate sets of vesicles at the trans-Golgi membrane[1], dendritic proteins are transported directly to the somatodendritic domain without entering the distal axonal domain, whereas axonal proteins enter both axons and dendrites[2]–[4]. Axonal proteins that are carried to the dendrites are unloaded onto the plasma membrane and subsequently reloaded into vesicles that travel to the axonal membrane[4],[5]. The net effect of these processes is that axonal transmembrane proteins are distributed roughly evenly to the intracellular regions of both the axon and dendrites, but are dramatically enriched on the axonal membrane. The transport of both axonal and dendritic proteins is mediated by kinesin motors[6]–[10]. However, targeting of dendritic proteins cannot be explained by the intrinsic properties of dendritic kinesins, such as Kif17, which cannot autonomously distinguish between axonal and dendritic microtubules[11]. Instead, recent work from our laboratory indicates that vesicles are targeted to dendrites through the actions of plus-end-directed myosin motors, which direct the vesicles away from the axon and towards the cell body[12]. This result suggests that a minus-end-directed motor might participate in the localization of axonal proteins. Interestingly, of the 35 known classes of myosin motors, members of only one, Myosin VI, are known to move towards the pointed( or minus) end of actin filament[13],. The involvement of Myosin VI in endocytosis further suggests that it might contribute to the enrichment of proteins on the surface of the axon. It associates with both clathrin-coated vesicles and proteins that mediate endocytosis[15]–[17] and plays a prominent role in the endocytosis of at least two neuronal proteins[18],[19]. Here, we show that Myosin VI[20] plays a role in the concentration of proteins at the axonal surface of neurons in dissociated cultures. Myosin VI mediates this axonal enrichment at least in part by enhancing dendrite-specific endocytosis. In addition, we find evidence that is consistent with Myosin VI promoting the direct trafficking of proteins to the axon. Thus, myosin motors contribute to the enrichment of both axonal and dendritic proteins at the plasma membranes of the appropriate polar compartments. In this manner they play a role in specifying the polarized structure of neurons, which is necessary for proper electrical signaling.
Discussion:
The data in this study indicate that Myosin VI plays a role in the enrichment of transmembrane proteins at the axonal surface. Myosin VI facilitates the relative enrichment of proteins at the surface of the axon by increasing the rate of endocytosis within the somatodendritic compartment relative to the axonal compartment. Overall, our results are consistent with a model whereby axonal proteins are transported by kinesin motors to both the axon and the dendrites following release from the Golgi apparatus( Figure S14). Following arrival of protein at the somatodendritic plasma membrane, it is endocytosed through the actions of Myosin VI. This participation of Myosin VI in dendritic endocytosis of axonal proteins is consistent with numerous reports documenting its role in endocytosis in epithelial cells and neurons as well as in nonpolarized cells[15],[18],[30],[31]. It remains to be determined the exact mechanism whereby specificity of Myosin VI action is achieved. It is possible that Myosin VI interacts either directly or indirectly with axonal proteins, or, alternatively, it is possible that Myosin VI interacts with the endocytic machinery associated with vesicles carrying these proteins[32]. In the future it will be important to fully explore this question. With the results of this study, there is now evidence that actin and myosin play pivotal roles in the concentration of proteins on the surface of either the axon or the dendrites; however, the role of microtubule-based mechanisms in these processes is less clear. A number of observations indicate that kinesin motors might be involved in steering vesicles to polarized compartments. For instance, the motor domain of Kif17, which transports dendritic proteins[6],[7], carries vesicles into the axon less efficiently than Kif5, which transports both axonal and dendritic proteins[33]. Tailless Kif5 targets to axons in a manner that is dependent on microtubule dynamics[11], and blocking Kif5 function with dominant negative constructs disrupts neuronal polarity[33]. Additionally, tyrosination, a phenomenon that occurs in dendrites, but not axons, causes Kif5 to bind at lower affinity to dendritic microtubules in comparison to those present in the axon[34],[35]. Finally, Kif5 prefers to bind to stable microtubules, which predominate in the axon, whereas other kinesins can also interact with unstable microtubules, which predominate in dendrites[36]. Although these experiments suggest that Kif5 has a bias towards axonal transport, it is also capable of carrying proteins such as GluR2 to the dendrites[8]. The work in this paper and our previous work would suggest that APP, which is also carried by Kif5[37], and GluR2 localize differently because APP is carried in vesicles that associate with active Myosin VI, whereas vesicles carrying GluR2 likely are influenced by the actions of a plus-end-directed Myosin, such as Myosin Va[12]. Nonetheless, our experiments do not rule out an active role for kinesins in polarized targeting. For instance, it has been shown that Kif5 likely plays a role in the initial establishment of neuronal polarity during early development in vitro when it carries C-Jun N-Terminal Kinase to the nascent axon[38],[39]. Thus, under certain circumstances, kinesin motors are capable of targeting specifically to one or the other polarized compartment. However, the results in this paper and our previous study[12] would indicate that in many cases contributions by myosin motors are required for polarized trafficking. In addition to kinesins, the dynein complex has also been suggested to participate in the polarized targeting of dendritic proteins, since causing organelles to link to dynein results in their transport specifically to dendrites[40]. While this effect is remarkably robust, it is not surprising given the fact that only dendrites contain microtubules that are oriented in a direction that permits movement of dynein away from the cell body and into the process[41]. Although blocking dynein with Dynamitin blocked dendritic targeting of GluR2, this disruption was not distinguished from the disruption of neuronal polarity in general. In contrast, blocking the function of Myosin Va or Myosin VI specifically disrupts the polarized distribution of subsets of proteins without destroying the overall polarity of the cell([12]; Figures 2 and S6–S8). Furthermore, the assertion that dendritic proteins are specifically transported by dynein motors and not by kinesins would appear to contradict numerous studies[6]–[8],[42]. A model where dynein plays a crucial role in the maintenance of the cytoskeletal structure that is essential for neuronal polarity, while myosin motors in combination with kinesins mediate trafficking, is consistent with both our work and that of others. Recent experiments support the existence of a vesicle filter dependent on actin within the axon initial segment. For instance, when large molecules are injected into the cell body of dissociated hippocampal neurons in culture, they are excluded from the axon in control neurons, but not in neurons exposed to Cytochalasin D, which promotes actin depolymerization[33]. Latrunculin B, which also promotes actin depolymerization, disrupts the localization of numerous polarized proteins including NgCAM[24]. Moreover, electron microscopy studies show the presence of actin filaments, albeit of indeterminate orientation, below the axolemma[43]. Our previous results suggested that this filter might play a role either in preventing entry of dendritic proteins into the axon[12],[44] or in promoting their entry into dendrites. In this study we found that a protein bound to Myosin VI( CD8-MVIBD) is localized intracellularly to both the axon and the dendrites( Figure S9), which would imply that there is nothing preventing it from entering the dendrites and thus that no vesicle filter exists in the proximal dendrites. In addition, a vesicle filter present in the axon initial segment that prevents proteins associated with Myosin Va from entering the axon would have the opposite effect on proteins associated with Myosin VI. Thus, Myosin VI might interact with actin filaments to guide vesicles containing axonal proteins and carried by kinesins towards the axon( Figure S14). The presence of a vesicle filter in only one compartment could explain why axonal and dendritic proteins are trafficked by distinct mechanisms in mammalian neurons:( 1) Axonal proteins associated with Myosin VI initially enter both compartments, but are concentrated in the axon in part through Myosin VI-dependent endocytosis from the dendritic plasma membrane.( 2) Vesicles carrying dendritic proteins, which associate with Myosin Va, are prevented from entering the distal axon by its vesicle filter, which causes the vesicles to be trafficked directly to the dendrites. In invertebrates, however, it appears that localization of both axonal and dendritic proteins depends on endocytosis from the plasma membrane of the opposite compartment. Thus, in Caenorhabditis elegans, several dendritic receptors including the acetylcholine receptor and a glutamate receptor are localized to dendritic membranes through axon-specific endocytosis, while Synaptogyrin is localized to the axon through endocytosis from the somatodendritic membrane[45],[46]. It seems likely that in the relatively compact neurons of invertebrates, endocytic mechanisms alone are sufficient to localize transmembrane proteins efficiently to the membrane of either the axon or the dendrite. Thus, it is tempting to speculate that the advent in vertebrates of neurons with very long, thin axons dramatically increased the cost of localization strategies dependent on endocytosis. This development might have exerted sufficient selective pressure to facilitate the formation of a cytoskeletal structure, the vesicle filter, which prevents vesicles containing dendritic proteins from entering axons and promotes the entry of vesicles containing axonal proteins.
Following synthesis in the endoplasmic reticulum ( ER ) and Golgi apparatus , neuronal proteins follow divergent trafficking pathways to the axonal and dendritic plasma membranes . This specialized trafficking depends on motor proteins that move along microtubules or actin in either a “plus-end” or “minus-end” direction . Although the molecular details of these pathways are poorly understood , recent work suggests that a plus-end-directed myosin motor guides proteins preferentially to dendrites . Here we find that Myosin VI , a minus-end-directed motor , plays a role in the concentration of proteins at the surface of the axon . Several studies have shown that many axonal proteins are targeted to both compartments initially , and are subsequently enriched on the axonal surface after they have been specifically removed from the surface of the dendrites by endocytosis . We show here that this dendrite-specific endocytosis is promoted by interaction with Myosin VI , whereas blocking Myosin VI function prevents axonal protein from being internalized from the surface of dendrites . Our results suggest a model where neuronal proteins are enriched on the surface of either axons or dendrites based on the properties of the myosin motor with which they interact .