SELECTED PUBLICATIONS

A ‘+’ designates Dr. Miller is the corresponding author.
A ‘*’ indicates the work was peer reviewed.

+ * Baqri RM, Pietron AV, Roossien DH, Gokhale RH, Turner BA, Kaguni LS,
Shingleton AW, Miller KE. TRAP1, a novel modulator of the Mitochondrial UPR, extends healthspan but not lifespan in Drosophila. Aging Cell. 2012; Under revision.

+ * Roossien DH, Lamoureux P, George AN, David Van Vactor D, Miller KE.
Axons elongate by bulk advance of the growth cone in Drosophila embryos in vivo 2012; Under review.

+ * Miller KE. Axons. Encyclopedia of Neuroscience. 2012; In press.

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 showcases my development of a novel 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 a quick overview as to why it is important to study axonal elongation, what is known about the problem, and where the field is heading, this is an excellent review. My primary contribution to this field is the development of a new model, the Stretch and Intercalated Growth (SAI) hypothesis. It proposes forces move the growth cone forward and stretch the axon while new mass is added along the axon to prevent thinning. My work is specifically discussed in sections 2.4 and 2.5 of this paper.

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- manuscript.
Lamoureux P., S. Heidemann and K.E. Miller, Mechanical Manipulation of Neurons to Control Axonal Development. Journal of Visualized Experiments , 2011- movie.
This JoVE video, starring my Research Assistant Phillip Lamoureux, describes how we use force calibrated micropipettes to measure and apply forces to neurons.

+ * 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.

In an attempt 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.