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Review
. 2011 Mar;93(3):313-40.
doi: 10.1016/j.pneurobio.2011.01.003. Epub 2011 Jan 7.

Multivesicular bodies in neurons: distribution, protein content, and trafficking functions

Christopher S Von Bartheld  1 , Amy L Altick
Affiliations
Review

Multivesicular bodies in neurons: distribution, protein content, and trafficking functions

Christopher S Von Bartheld et al. Prog Neurobiol. 2011 Mar.

Abstract

Multivesicular bodies (MVBs) are intracellular endosomal organelles characterized by multiple internal vesicles that are enclosed within a single outer membrane. MVBs were initially regarded as purely prelysosomal structures along the degradative endosomal pathway of internalized proteins. MVBs are now known to be involved in numerous endocytic and trafficking functions, including protein sorting, recycling, transport, storage, and release. This review of neuronal MVBs summarizes their research history, morphology, distribution, accumulation of cargo and constitutive proteins, transport, and theories of functions of MVBs in neurons and glia. Due to their complex morphologies, neurons have expanded trafficking and signaling needs, beyond those of "geometrically simpler" cells, but it is not known whether neuronal MVBs perform additional transport and signaling functions. This review examines the concept of compartment-specific MVB functions in endosomal protein trafficking and signaling within synapses, axons, dendrites and cell bodies. We critically evaluate reports of the accumulation of neuronal MVBs based on evidence of stress-induced MVB formation. Furthermore, we discuss potential functions of neuronal and glial MVBs in development, in dystrophic neuritic syndromes, injury, disease, and aging. MVBs may play a role in Alzheimer's, Huntington's, and Niemann-Pick diseases, some types of frontotemporal dementia, prion and virus trafficking, as well as in adaptive responses of neurons to trauma and toxin or drug exposure. Functions of MVBs in neurons have been much neglected, and major gaps in knowledge currently exist. Developing truly MVB-specific markers would help to elucidate the roles of neuronal MVBs in intra- and intercellular signaling of normal and diseased neurons.

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Figures

Fig. 1
Fig. 1. A-E Examples of multivesicular bodies (MVBs) in neurons at the ultrastructural level
A. Two profiles of MVBs (arrows) in a neuronal soma. The MVBs have a single limiting outer membrane, unlike the double membrane of mitochondria (M). The MVBs contain internal vesicles of homogeneous size. B. This MVB is located near the cell nucleus (N), the endoplasmic reticulum (ER) and the Golgi apparatus (G). C and D. Dendritic MVBs in close vicinity of presynaptic terminals (S), a preferred location of MVBs (Rind et al., 2005). Note the varying amount of internal vesicles within MVBs. The internal vesicles in the dendritic MVB have a similar diameter as the synaptic vesicles (SV). E. MVB within a myelinated axon; my = myelin sheath. All images are from postnatal rat brain hypoglossal motoneurons. Scale bars A-E = 250 nm.
Fig. 2
Fig. 2. A-D. Trophic factors accumulate in neuronal MVBs of the soma and dendrites after axonal transport
A. The radiolabeled trophic factor GDNF, visualized by an autoradiographic silver grain, localizes within an MVB of a hypoglossal motoneuron dendrite after retrograde axonal transport of the GDNF from the tongue muscle and after trans-somal transport, likely within an MVB, to reach the dendrite. B. In the soma, radiolabeled trophic factor BDNF localizes in a MVB after retrograde transport from motoneuron terminals. C. MVBs located in close vicinity of postsynaptic densities of a synapse (S) contain the radiolabeled trophic factor GDNF that arrived there by retrograde axonal transport, followed by transport across the soma and apparently along microtubules (mt) into the dendrite. D. Example of a dendritic MVB that accumulated the radiolabeled trophic factor NT-3, following internalization of this trophic factor by retinal ganglion cells and anterograde axonal transport along the optic nerve to the midbrain tectum. The radiolabeled NT-3 crossed the retinotectal synapse to accumulate in an MVB within the postsynaptic dendrite. Panel D was reproduced with permission (von Bartheld et al., 1996). Abbreviations: M, mitochondrion; mt, microtubule; S, synapse. Scale bars A-D = 200 nm.
Fig. 3
Fig. 3. A-C. Neurotrophic factors reside primarily on the outer membrane of MVBs in dendrites, but inside MVBs located in the soma
A. Example of a silver grain (asterisk) representing the trophic factor BDNF residing on the outer membrane of a dendritic MVB. B. Example of a silver grain representing the trophic factor GDNF residing on the inside (asterisk) of a somal MVB. C. The location of silver grains was quantified in a histogram for a total of 119 silver grains representing either radiolabeled BDNF or GDNF that were injected in the tongue muscle and transported retrogradely to the soma and dendrites of hypoglossal motoneurons (Rind et al., 2005). The method (LaVail et al., 1983) relies on measuring the distance of the center of silver grain from the outer membrane, plotted separately for dendritic and somatic MVBs. The data for BDNF and GDNF was combined, as there was no significant difference between the two data sets. Somal and dendritic MVBs showed statistically significant differences in trophic factor location. Panel C was reproduced with permission (Rind et al., 2005). Scale bars in A, B = 250 nm.
Fig. 4
Fig. 4. MVB biogenesis and three possible MVB sorting pathways: exosome release (1), back fusion/recycling (2), and degradation (3)
Left side: Endosome formation with membrane invagination to form internal vesicles. Center: The MVB may progress through one of three maturation or sorting stages: (1) The limiting membrane of the MVB may fuse with the plasma membrane and release internal vesicles as exosomes. (2) The MVB may extend tubular processes formed by membranes from internal vesicles. The tubular extensions “back-fuse” to insert limiting membrane into the cell surface membrane, thereby recycling ligand/receptor to the plasma membrane. (3) MVBs can target internalized ligand/receptors for degradation in the lysosome either by fusion with lysosomes or maturation into a lysosome. None of these three pathways have been directly demonstrated in neurons, but there is suggestive evidence from non-neuronal cell types. For details on exosomes and back fusion, see Faure et al., 2005; Fevrier et al., 2004; Harding, et al., 1983; Murk et al., 2002; and Putz et al., 2008. For maturation, see Murphy, 1991; van Deurs et al., 1993; for fusion/sorting, see Gruenberg et al., 1989; Mullock et al., 1998; Vonderheit & Helenius 2005. Red square: ligand; blue dot: cytoplasmic domain of receptor; black: transmembrane domain of receptor; white circle: internal vesicle.
Fig. 5
Fig. 5. A-D. Dynamic MVB morphology suggestive of biogenesis and recycling
Examples of neuronal MVBs with invaginations (A) or tubular extensions (B-D). The limiting membranes and internal vesicles are outlined for clarity in the lower panel, with arrows pointing to the invagination or tubular extension. These MVB forms indicate biogenesis or membrane recycling according to the biogenesis and back-fusion models of MVB functions (Murk et al., 2002). Note that the MVB is nearly devoid of internal vesicles in the area next to the tubular extension, consistent with the notion that the tubular extensions are generated by fusion of internal vesicles with the limiting membrane. For other examples of neuronal MVBs in transition, see Roizin et al., 1967. Scale bar A-D = 250 nm.
Fig. 6
Fig. 6. Synopsis of known and potential MVB trafficking pathways in neurons
Different types of MVBs may be involved in different trafficking patterns within neurons, numbered from 1 to 4 as indicated in the legend. Routes are based on presumed or known pathways (1-3, solid lines) as shown in studies tracking internalized markers and their localization within neuronal MVBs. There is no indication that MVBs move along axons in the anterograde direction (4, stippled); all other pathways are either proven or likely (solid lines). Evidence is primarily based on Altick et al., 2009; Cooney et al., 2002, LaVail and LaVail, 1974; Parton et al., 1992; and Rind et al., 2005.
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