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The Role of Microtubule Movement in Bidirectional Organelle Transport

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The Role of Microtubule Movement in Bidirectional Organelle Transport The role of microtubule movement in bidirectional organelle transport Igor M. Kulic´*†, Andre´ E. X. Brown‡, Hwajin Kim§, Comert Kural¶, Benjamin Blehm¶, Paul R. Selvin¶, Philip C. Nelson‡, and Vladimir I. Gelfand§ *School of Engineering and Applied Sciences, 29 Oxford Street, Pierce Hall 409, Harvard University, Cambridge, MA 02138; ‡Department of Physics and Astronomy and Nano/Bio Interface Center, University of Pennsylvania, Philadelphia, PA 19104; §Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and ¶Physics Department and Biophysics Center, University of Illinois at Urbana–Champaign, Urbana, IL 61801 Edited by James A. Spudich, Stanford University School of Medicine, Stanford, CA, and approved May 1, 2008 (received for review January 2, 2008) We study the role of microtubule movement in bidirectional between the peroxisomes and microtubules can be established. organelle transport in Drosophila S2 cells and show that EGFP- This finally leads us to a proposed model that integrates the tagged peroxisomes in cells serve as sensitive probes of motor dynamic interplay of vesicle motion, molecular motor action, and induced, noisy cytoskeletal motions. Multiple peroxisomes move in microtubule motility. unison over large time windows and show correlations with microtubule tip positions, indicating rapid microtubule fluctua- Results tions in the longitudinal direction. We report the first high-reso- Behavior of Single and Multiple Peroxisomes in Vivo. In a previous lution measurement of longitudinal microtubule fluctuations per- study of GFP-labeled peroxisome motion in Drosophila S2 cells, formed by tracing such pairs of co-moving peroxisomes. The Kural et al. (11) demonstrated a velocity distribution exhibiting resulting picture shows that motor-dependent longitudinal micro- a significant contribution of very large velocities (Ͼ10 ␮m/s) tubule oscillations contribute significantly to cargo movement over larger time intervals (several tens of milliseconds). We have along microtubules. Thus, contrary to the conventional view, reanalyzed some of these extreme velocity events. Often such organelle transport cannot be described solely in terms of cargo fast movements were preceded or followed by rapid movements movement along stationary microtubule tracks, but instead in- in the opposite direction (in 32 of 36 or 89% of trajectories, cludes a strong contribution from the movement of the tracks. lasting for at least 10 s) with subsecond time intervals between direction-switching events—a characteristic signature of bidirec- intracellular transport ͉ molecular motors ͉ kinesin ͉ dynein ͉ cytoskeleton tional transport. Whereas nonsteady relaxing velocities were characteristic of olecular motor-mediated transport along microtubules is 89% of 36 motile particle trajectories, single exponential velocity Man extensively studied phenomenon in vitro (1–3). Despite decays over intervals Ͼ100 ms as shown in Fig. 1a (Inset, blue significant advances in vitro, understanding how intracellular curve) were rare [in 9 of 36 or 25% of trajectories; see supporting transport works in vivo still remains one of the big challenges in information (SI) Text]. Instead, a more complex behavior, cell biology. The question of how cellular cargos find their way including the superposition of multiple relaxation times and through the cytoplasm and get targeted to their temporary or direction-switching events, was predominant (Fig. 1 a and b). final destinations lies at the heart of the problem. One of the These velocity relaxation events indicated the presence of an major puzzles in this context is the so-called bidirectional elastic component in the system and suggested that bent and organelle transport. The majority of cargos in the cell move in a buckled microtubules could influence peroxisome transport. bidirectional and often remarkably symmetric manner (4, 5). This hypothesis was further strengthened by the observation of Despite the known kinetic and dynamic asymmetry of the several vesicles moving in concert (Fig. 1b) with strong velocity underlying plus- and minus-end directed microtubule motors, cross-correlation on timescales Ͼ30 ms (Fig. 1b Inset). the vesicles seem to move with the same rates and run length Because of the limited number of peroxisomes observed in distributions, and exhibit identical stalling forces, in each direc- close proximity to other peroxisomes (14 observations of per- tion (4–7). Furthermore, inhibition of transport in one direction oxisomes closer than 5 ␮m), the observation of co-moving typically results in the inhibition of movement in the opposite peroxisome pairs was rare (three observations). This is consis- direction as well (4–11). tent with the expectation that the large number of microtubules One straightforward explanation of bidirectional organelle per process (NMT Ϸ 5–10, determined by counting the micro- transport rests on the hypothesis (4–11) that a dedicated mo- tubules converging and entering the processes) reduces the lecular mechanism couples opposite polarity microtubule mo- probability of two peroxisomes to be found on the same micro- tors in vivo. Although this is possible, we suggest an alternative, tubule [P ϭ 1/(N Ϫ 1) Ϸ 10–25%]. However, those peroxi- perhaps complementary hypothesis to the motor coupling hy- MT somes moving in concert stayed in the highly correlated state for pothesis. Our hypothesis rests on the plausible assumption that longer than our observation time of 20 s (10,000 frames). Despite a cargo vesicle has multiple motors residing on it and that these the large (Ͼ90%) velocity correlation of peroxisome pair-speeds couple to several microtubules at a time. The conflicting strains cause them to slide, bend, and buckle, causing effective aperiodic limited-amplitude fluctuations. These fluctuations modify the Author contributions: I.M.K., P.R.S., P.C.N., and V.I.G. designed research; H.K., C.K., and B.B. motion of vesicles in an additive manner, contributing to the performed research; I.M.K., A.E.X.B., and C.K. analyzed data; and I.M.K., A.E.X.B., P.R.S., phenomenology of bidirectional organelle transport. We de- P.C.N., and V.I.G. wrote the paper. scribe unusual observations coming from high-resolution traces The authors declare no conflict of interest. of single peroxisomes, in particular, the unusual mean-square This article is a PNAS Direct Submission. displacement (MSD) behavior and large velocity cross- †To whom correspondence should be addressed. E-mail: [email protected]. correlation observed between peroxisomes. We then present This article contains supporting information online at www.pnas.org/cgi/content/full/ results from simultaneous two-color imaging of peroxisomes and 0800031105/DCSupplemental. CELL BIOLOGY microtubules. It is shown that in many cases a strong correlation © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0800031105 PNAS ͉ July 22, 2008 ͉ vol. 105 ͉ no. 29 ͉ 10011–10016 Downloaded by guest on October 1, 2021 6 1.8 a 4.8 b 4.6 1.6 Fig. 1. Unusual dynamical features of peroxisomes 5 4.4 1.4 moving in S2 processes. (a) Typical displacement vs. 4.2 time of peroxisomes along the microtubule direction, 4 1.2 1.9 2 2.1 characterized by nonconstant velocities, indicates the m] m] 1 involvement of microtubule elastohydrodynamics. In µ µ 3 1 ) [ 0.8 some cases the initial relaxations were extremely rapid x(t) [ 0.8 x(t 1 (Ϸ12 ␮m/s) but quickly slowed down and were well 0.6 2 2 0.6 fitted by single exponentials (blue curve and Inset, 610 0.4 0.4 nm total length release, 60 ms relaxation time). (b) 1 0.2 0.2 2µm CG Time [s] Two peroxisomes (Left Inset) move almost perfectly in 0 0 0.2 0.4 0.6 0.8 1 concert over a large time window (see Movie S1). The 0 0 0 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 vertical axis is displacement of the peroxisome center Time [s] Time [s] along the axis shown as a dashed line in Left Inset. The initial displacements are shifted to facilitate the com- parison. (Right Inset) The velocity cross-correlation (y 7 8 α c 10 10 d 10 axis) of the two particles as a function of the coarse- 8 6 6 graining (CG) time (the time interval over which the 10 6 10 mean velocities are evaluated) on the horizontal axis. 4 4 ] 10 Ͻ 2 5 On short times ( 30 ms) the vesicles undergo individ- 10 2 3/2 ual uncorrelated dynamics whereas on longer times 102 4 1/2 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 (Ͼ100 ms) they become strongly correlated. (c) The 10 101 103 β 10 MSD of the vesicles from b vs. time shows power-law MSD [nm β 3 10 t 8 scaling with a subdiffusive exponent (0.82 and 0.70) 6 for times Ͻ30 ms and from 100 ms to3sahyperdif- 2 10 fusive exponent (1.47 and 1.49). (Inset) MSD vs. time of α Number of observations 4 t 2 representative traces (thick lines indicate the slopes 0.5 1 10 and 1.5). (d) The distribution of short-time and long- 10 0 101 102 103 104 105 0.8 1 1.2 1.4 1.6 1.8 2 time scaling exponents of the MSD from n ϭ 36 per- Lag Time [ms] MSD scaling exponent oxisomes (␣ ϭ 0.59 Ϯ 0.28, and ␤ ϭ 1.62 Ϯ 0.29). (Fig. 1b Inset), their relative distance was not strictly constant and another (see Fig. 1b), moving in concert on this short and, in fact, was slowly changing in time (by 220 nm over 20 s). timescale (as opposed to their high correlation on long time- A systematic analysis of peroxisomes in thin processes of S2 scales), indicate that local environment effects and thermal cells showed two different types of moving behaviors: (i)A fluctuations dominate the peroxisome motion at very short population of relatively immobile particles (25 of 61 or Ϸ40% of timescales rather than an active driving force (i.e., microtubule the total population), moving Ͻ100 nm during a 5-s interval, motors).
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