PUBLICATIONS A ‘+’ designates Dr. Miller is the corresponding author. + * McElmurry, K., J.E. Stone, D. Ma, P. Lamoureux, Y. Zhang, M. Steidemann, L. Fix, F. Huang, K.E. Miller, and D.M. Suter. Dynein-mediated microtubule translocation powering neurite outgrowth requires microtubule assembly. J. Cell Sci., 2020, 133(8). + * Badal, K.K., K. Akhmedov, P. Lamoureux, X.A. Liu, A. Reich, M. Fallahi-Sichani, S. Swarnkar, K.E. Miller, and S.V. Puthanveettil. 2019. Synapse Formation Activates a Transcriptional Program for Persistent Enhancement in the Bidirectional Transport of Mitochondria. Cell reports. 26:507-517 e503. + * Miller, K.E. and D.M. Suter, An Integrated Cytoskeletal Model of Neurite Outgrowth. Front Cell Neurosci, 2018. 12: p. 447. + * de Rooij, R., E. Kuhl, and K.E. Miller, Modeling the Axon as an Active Partner with the Growth Cone in Axonal Elongation. Biophys J, 2018. 115(9): p. 17831795. + * de Rooij, R., K.E. Miller, and E. Kuhl, Modeling molecular mechanisms in the axon. Comput Mech, 2017. 59(3): p. 523-537. + * Athamneh, A.I.M., et al., Neurite elongation is highly correlated with bulk forward translocation of microtubules. Sci Rep, 2017. 7(1): p. 7292. + * Halievski, K., et al., Non-Cell-Autonomous Regulation of Retrograde Motoneuronal Axonal Transport in an SBMA Mouse Model. eNeuro, 2016. 3(4): p. ENEURO. 0062-16.2016. + * Miller, K. E., Liu, X., and Puthanveettil, S.V. (2015). Automated measurement of fast mitochondrial transport in neurons. Front Cell Neurosci, 2015. 9: p. 435. + * O'Toole, M., Lamoureux, P., and Miller, K.E. (2015). Measurement of subcellular force generation in neurons. Biophys J 108, 1027-1037. Here we develop a method that allows, for the first time, a means to directly measure sub-cellular force generation. + * Roossien, D.H., Miller, K.E., and Gallo, G. (2015). Ciliobrevins as tools for studying dynein motor function. Front Cell Neurosci 9, 252. This is the first focused review of the selective cell permeable dynein inhibitor ciliobrevin. * Holland, M.A., Miller, K.E., and Kuhl, E. (2015). Emerging Brain Morphologies from Axonal Elongation. Ann Biomed Eng 43, 1640-1653. + * Roossien, D.H., Lamoureux, P., and Miller, K.E. (2014). Cytoplasmic dynein pushes the cytoskeletal meshwork forward during axonal elongation. J Cell Sci 127, 3593-3602. Here we demonstrate that pushing forces associated with microtubules in neurons arises through the activity of dynein. + * Baqri, R.M., Pietron, A.V., Gokhale, R.H., Turner, B.A., Kaguni, L.S., Shingleton, A.W., Kunes, S., and Miller, K.E. (2014). Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila. Mech Ageing Dev 141-142, 35-45. + * Roossien, D.H., Lamoureux, P., Van Vactor, D., and Miller, K.E. (2013). Drosophila growth cones advance by forward translocation of the neuronal cytoskeletal meshwork in vivo. PLoS One 8, e80136. Two long-standing questions are whether the physical mechanism of axonal elongation is conserved between species and if in vitro studies of elongation are relevant to elongation in vivo. Here we show that fly neurons, like chick sensory neurons, lengthen by bulk forward flow of the cytoskeletal meshwork and that this mechanism of growth occurs in neurons grown in vitro on endogenous Drosophila Extracellular Matrix Proteins (DECM). Thus the physical mechanism of elongation appears to be highly conversed between species and occurs by bulk forward advance in vivo. + * Miller KE. Axons. Encyclopedia of Neuroscience. 2012. This is a brief general review on axons. * Kemp M. Q., Poort J. L, Baqri R. M., Lieberman A. P., Breedlove S. M., Miller K. E., and C. L. Jordan. Impaired motoneuronal retrograde transport in two models of SBMA implicates two sites of androgen action. Human Molecular Genetics, 2011. 20:4475. This paper shows my development of a means, using confocal microscopy on an ex vivo preparation, to directly visualize organelle transport in the sciatic nerves of adult transgenic mice. Click to view movies. + * Suter D. M. and K.E. Miller, The Emerging Role of Forces in Axonal Elongation. Progress in Neurobiology, 2011. 94:91. If you are interested in an overview as to why it is important to study axonal elongation and where the field is heading, this is a solid review. Abu-Nimeh FT, Miller KE, Salem FM. On-chip Autonomous Axonal Elongation. Nano Imaging and Manipulation, EEE International Solid-State Circuits. 2011;Conference Proceedings, 2011. This presentation describes our success in testing a microchip that can be used to manipulate magnetic beads that can be bound to neurons. Click to view a movie of the chip in action. + * Lamoureux P., S. Heidemann and K.E. Miller, Mechanical Manipulation of Neurons to Control Axonal Development. Journal of Visualized Experiments , 2011. This JoVE video, starring my Research Assistant Phillip Lamoureux, describes how we use force calibrated micropipettes to measure and apply forces to neurons. Click Here to view the movie. + * O'Toole M. and K.E. Miller, The Role of Stretching in Slow Axonal Transport. Biophysical Journal, 2011. 100:351. A long standing paradox in neurobiology is that axons can elongate many times faster than the rate proteins are transported along the axon. Theoretically, it takes 35 years for proteins to move from the spinal cord to the big toe in adult humans, yet adult height is normally reached 15 years earlier. In this paper, Matthew and I develop a mathematical model that may help resolve this paradox. + * Lamoureux P., M. O'Toole, S. Heidemann and K.E. Miller, Slowing of axonal regeneration is correlated with increased axonal viscosity during aging. BMC Neuroscience, 2010. 11:40. As we age, it is well accepted that our bodies and mind become less flexible. In this biophysical analysis we demonstrate that individual neurons become mechanically stiffer during aging. We speculate that this, in part, underlies the slow rate of axonal regeneration in adults. The implication of this work is that alternation of the biomechanical properties of axons may enhance the rate of axonal regeneration. + * Lamoureux, P., S. R. Heidemann, N. R. Martzke, and K. E. Miller, Growth and Elongation Within and Along the Axon. Dev Neurobiol. 2010. 70:135-49. The hypothesis that microtubule polymerization drives growth cone advance arose, in part, from experiments conducted in the 70s that indicated that axonal branch points and beads bound to the axon are stationary relative to the substrate. Using the same type of neuron, grown on the same type of substrate, we find beads, branch points, and docked mitochondria are stationary near the cell body, but move forward in the distal axon. Based on these findings, in this paper, we propose our Stretch and Intercalated Growth (SAI) hypothesis. See Suter and Miller, 2011 for a review. Movie 1. Branch point movement in a chick sensory neuron grown on laminin. Phase images are on the left, fluorescent images of mitochondria are on the right. Note that docked mitochondria advance in tandem with the branch point. Movie 2. Bead movement in a chick sensory neuron grown on laminin. + * Baqri, R. M., B. A. Turner, M. B. Rheuben, B. D. Hammond, L. S. Kaguni, and K. E. Miller, Disruption of Mitochondrial DNA Replication in Drosophila Increases Mitochondrial Fast Axonal Transport In Vivo. PLoS one, 2009. 4(11): e7874. To better understand the life cycle of mitochondria in neurons, we generated fruit flies (Drosophila Melanogaster) that could not make mitochondrial DNA. We then monitored kinesin and dynein based mitochondrial movement in vivo in Drosophila larvae. Since mitochondrial DNA is necessary for mitochondrial ATP production, we hypothesized that mitochondrial trafficking would be severely disrupted. Thus, we were quite surprised to find that kinesin and dynein mediated mitochondrial transport in neurons doubled. We suggest this occurs as part of an SOS response that activates both mitochondrial biogenesis and transport in response to low ATP levels. While these findings were unexpected, they are intuitive in that they suggest cells sense mitochondrial ATP production and when it is low respond by increasing the production and transport of new mitochondria. Movie of mitochondrial transport in wildtype (top) and pol-gamma null (bottom) 3rd instar Drosophila larvae. + * O'Toole, M., R. Latham, R. Baqri, and K.E. Miller, Modeling Mitochondrial Dynamics During In Vivo Axonal Elongation. J. Theoretical Biology, 2008. 255(4) p. 369-377. My post-doctoral work in the lab of Michael Sheetz at Columbia University suggested that new mitochondria are made in the neuronal cell body, are transported out to the axon, search back and forth along the axon for a place that needs ATP generation, dock, make ATP, and then upon being damaged are transported back to the cell body for degradation. As a means to better understand this hypothesis, we developed a mathematical model of the mitochondrial lifecycle in Drosophila larvae that incorporates the rates of mitochondrial creation, destruction, and transport along axons that are lengthening through stretching. This model was based on direct observation of mitochondrial transport and distribution in Drosophila larvae. One interesting implication of this work is that it appears that neurons possess a mechanism that controls mitochondrial transport and biogenesis in response to changes in axonal length. + * O'Toole, M., P. Lamoureux, and K.E. Miller, A physical model of axonal elongation: force, viscosity, and adhesions govern the mode of outgrowth. Biophys J, 2008. 94(7): p. 2610-2620. In the most interesting sorts of controversies, there is strong experimental data that supports each case. Moving forward requires a proper acknowledgement and reconciliation of the seemingly conflicting data. In this paper, Mathew and I formulate a mathematical model that suggests biophysical parameters control whether neurons grow by microtubule polymerization in the growth cone or by stretching of the axon. Coupled with this modeling, we measure neuronal force generation, axonal viscosity, and the strength of adhesions between the axon and substrate. Of note, this paper has the honor of being cited on the Wikipedia page for growth cones (http://en.wikipedia.org/wiki/Growth_cone). + * Miller, K.E. and S.R. Heidemann, What is slow axonal transport? Exp Cell Res, 2008. 314(10): p. 1981-1990. A: Slow axonal transport is the process by which cytoskeletal and soluble proteins are distributed in axons. What has intrigued generations of scientists is how it occurs at a mechanistic level. In this review, I suggest that there are multiple mechanisms that simultaneously contribute including: Stop and Go transport of polymerized cytoskeletal proteins, active transport of soluble cytoskeletal proteins, bulk transport as the result of axonal stretching, and diffusion. The implication of this work is that a careful accounting of the various modes of the transport at different time points during elongation needs to be conducted to fully understand how cytoskeletal proteins are delivered to growing and mature axons. * Miller, K.E. and D. Van Vactor, Liprin-alpha and Assembly of the Synaptic Cytomatrix. Encyclopedia of Neuroscience, 2007. 4(1). Scaffolding proteins, such a Liprin-alpha, seem to have no obvious function other than binding to multiple other proteins. Nonetheless, when they are disrupted cellular function can be dramatically impaired. Metaphorically, they seem to serve a role that is similar to scientific meetings: they bring multiple parties together to facilitate the exchange of information. In this book chapter, we briefly review the scaffolding protein Liprin-alpha in the context of synaptic functioning and axonal transport. + * Miller, K.E. and M.P. Sheetz, Direct evidence for coherent low velocity axonal transport of mitochondria. J Cell Biol, 2006. 173(3): p. 373-381. As a graduate student, I strongly supported the theory that axons elongate by microtubule polymerization at the growth cone. Nonetheless in hours of time lapse videos where I monitored mitochondrial trafficking during axonal elongation, I observed what I felt was a shocking pattern of movement. Mitochondria that were docked in the growth cone advanced with the growth cone. Furthermore, docked mitochondria along the length of the axon moved forward in a pattern indicative of axonal stretching. This ran contrary to the hypothesis that microtubules are stationary along the axon, new segments of axons are built through microtubule polymerization, and fast transport delivers new mitochondria to the growth cone. The data in this paper suggested a new way of thinking about the long standing question of how axons grow that is now the current focus of my research program. * Miller, K.E., J. DeProto, N. Kaufmann, B.N. Patel, A. Duckworth, and D. Van Vactor, Direct observation demonstrates that Liprin-alpha is required for trafficking of synaptic vesicles. Curr Biol, 2005. 15(7): p. 684-689. Whether vesicular transport is controlled through the specific regulation of kinesin and dynein activity or arises as the result of a tug-of-war continues to be actively debated. In this paper, I developed methods to visualize the axonal transport of synaptic vesicle precursors in vivo in Drosophila larvae, then assessed the role of the scaffolding protein Liprin-alpha in axonal transport. Our findings suggested that Liprin-alpha promotes the delivery of synaptic material by a direct increase in kinesin processivity and an indirect suppression of dynein activation. * Miller, K.E. and M.P. Sheetz, Axonal mitochondrial transport and potential are correlated. J Cell Sci, 2004. 117(Pt 13): p. 2791-2804. * De Vos, K.J., J. Sable, K.E. Miller, and M.P. Sheetz, Expression of phosphatidylinositol (4,5) bisphosphate-specific pleckstrin homology domains alters direction but not the level of axonal transport of mitochondria. Mol Biol Cell, 2003. 14(9): p. 3636-3649. * Miller, K.E. and M.P. Sheetz, Characterization of myosin V binding to brain vesicles. J Biol Chem, 2000. 275(4): p. 2598-2606. + * Miller, K.E. and D.C. Samuels, The axon as a metabolic compartment: protein degradation, transport, and maximum length of an axon. J Theor Biol, 1997. 186(3): p. 373-379. * Miller, K.E. and H.C. Joshi, Tubulin transport in neurons. J Cell Biol, 1996. 133(6): p. 1355-1366. * Harris, R.J., J.D. Jasper, B.C. Lee, K.E. Miller, Consenting to donate organs: whose wishes carry the most weight? Journal of Applied Social Psychology, 1991. 21(1), p. 3-14. * Jasper J.D., R.J. Harris, B.C. Lee, K.E. Miller, Organ donation terminology: Are we communicating life or death? Health Psychology, 1991. 10(1), p. 34-41. |