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.
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.
Mechanical Manipulation of Neurons to Control Axonal Development. Journal of Visualized Experiments , 2011- manuscript.
Lamoureux P., S. Heidemann and K.E.
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.
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
+ * Lamoureux P., M. O'Toole, S. Heidemann and K.E.
Slowing of axonal regeneration is correlated with increased axonal viscosity during aging. BMC Neuroscience, 2010. 11:40.
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
+ * 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.
Movie 1. Branch point movement in a chick sensory neuron grown on laminin.
The hypothesis that microtubule
polymerization drives growth cone advance arose, in part, from
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.
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.
an attempt to better
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
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
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
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.
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
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
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
* 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.
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):
* Miller, K.E. and
H.C. Joshi, Tubulin transport in neurons. J Cell Biol, 1996. 133(6): p.
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.