Kenneth G. Miller, Ph.D.
Genetic Models of Disease Research Program
Adjunct Professor, Oklahoma Center for Neuroscience
In terms of human health, my laboratory at the Oklahoma Medical Research Foundation contributes to understanding the genetic basis of human neurodegenerative disorders such as ALS, hereditary spastic paraplegia, and Charco-Marie-Tooth peripheral neuropathy.
My laboratory’s specific research mission is to understand how nerve cells control the movements of cargoes within and between their long extensions, which are known as axons and dendrites. Cargos in all cells are transported along a system of microtubule tracks using tiny molecular motors that literally walk rapidly along the tracks, carrying the cargo. This transport system is especially important for nerve cells because of their complicated shapes and long extensions.
Nerve cells send tiny synaptic vesicle cargoes long distances into the axon where they accumulate in stable clusters at sites known as synapses. The synaptic vesicle clusters are very important because they are used to send signals to other nerve cells and muscle cells. These signals form the basis for our perceptions, movements, thoughts, and memories. Nerve cells need to prevent motor proteins from taking synaptic vesicles from the clusters back to the cell soma. In contrast, other larger cargoes, known as organelles, must be kept away from synapses and sent back to the main cell body so they don’t interfere with signaling. We recently discovered the system that neurons use to regulate motor activity to promote organelle clearance from axons while at the same time protecting synaptic vesicle clusters at synapses (see “Research”).
Since neurons function the same way in all animals, we study cargo transport using the model organism C. elegans, where we can perform complex experiments that would be impossible in other systems, such as mice and humans. C. elegans is a 1 mm long roundworm that has a simple nervous system with only 300 nerve cells and 5000 synapses. We can “tag” a cargo, such as an organelle or a synaptic vesicle, with a fluorescent protein and watch the cargo move from one part of the neuron to another part in living animals using high power microscopes.
The C. elegans model also allows us to use advanced genetic techniques to investigate cargo transport. One of the most powerful strategies for understanding “how things work” in biology is to intentionally mutate a model organism, such as C. elegans, and identify mutants that disrupt whatever process you are studying. In my lab we use many different kinds of mutant screens, each of which involves examining thousands of individual animals to identify mutants defective in cargo transport. For example, we might screen for mutants in which fluorescently tagged organelles accumulate abnormally in the synaptic region. We then map the mutations to specific genes to identify the specific proteins that are important for regulating organelle transport. This is known as a forward genetic screen. We can also start with a mutant that is defective in cargo transport and screen for mutations that suppress the defect. This is one way to identify genes that would be good drug targets for correcting transport defects related to human disease.
B.S., Houghton College, Houghton, NY, 1985
Ph.D., Stanford University, Stanford, CA, 1993
Honors and Awards
1993-1996 Individual National Research Service Award (NIH)
American Society for Cell Biology
Genetics Society of America
Society for Neuroscience
Joined OMRF Scientific Staff in 1993.
My lab currently studies the axonal transport system that neurons use to control how organelles and vesicles are distributed in different regions. The neuron’s axonal transport system consists of microtubule tracks and motor proteins that carry cargoes along the tracks, as well as proteins that regulate the transport. Microtubules have an intrinsic plus- and minus-end polarity, and axonal microtubules are oriented with their plus ends pointing outward (away from the cell soma). Plus-end directed motors from the large family of kinesins carry cargoes outward, while the minus-end motor dynein moves them in the opposite direction. Several neurodegenerative disorders in mice and humans are associated with mutations in the axonal transport machinery, a fact that underscores the importance of a properly functioning transport system for the long-term viability of neurons.
The long extensions of neurons (known as axons and dendrites) pose immense challenges for transporting organelles. For example, synaptic vesicles (SVs) must travel long distances into axons where they must accumulate in stable clusters at synapses to promote signaling between neurons, while cell soma organelles, such as Golgi, lysosomes, and some classes of endosomes, are often selectively cleared from the synaptic region where they could interfere with signaling. However, under special conditions of growth or repair, neurons may require cell soma organelles in their axons.
Our studies in C. elegans revealed that the conserved protein UNC-16 (known as JIP3 in humans) has a clearance function that drives cell soma organelles (lysosomes, endosomes, and Golgi) toward microtubule minus ends to keep them in or near the cell soma and dendrite and away from the synaptic region. Through a genetic suppressor screen, we recently discovered that JIP3 acts by blocking the function of a kinase known as CDK-5 (Cdk5 in humans) and two conserved “active zone” proteins: SAD-1 (SAD-A Kinase) and SYD-2 (Liprin-α). CDK-5, SAD-1, and SYD-2 are all part of the same system, which we named the CSS system based on its founder proteins. Our data show that the CSS system includes a subset of active zone proteins that normally prevents SV clusters and DCVs from getting transported back to the cell soma by dynein.
By screening for other mutants with similar phenotypes we identified a novel protein that is conserved from worms to humans. We named the new protein Sentryn based on its Sentry function of protecting SV clusters, but it also regulates organelle transport like other CSS system proteins. Sentryn is the first new active zone protein to be identified in 11 years. Our finding that a subset of active zone proteins also have general roles in organelle transport in neurons is completely unprecedented and opens up a new area of research.
A synthesis of our new findings with past studies in other systems suggests a new model for the regulation of axonal organelle transport: JIP3 promotes organelle clearance by blocking the CSS system, which, in the absence of JIP3, disrupts the connection between the dynein minus-end motor and organelles. We are now testing the JIP3/ CSS model and performing experiments to develop a mechanistic understanding of JIP3’s organelle clearance function and the CSS system.
By combining the in vivo relevance of genetic approaches and live animal imaging with the mechanistic relevance of model-guided proteomic and biochemical approaches in C. elegans and vertebrates, we hope to transform these entry point discoveries into fundamental insights about how neurons regulate organelle transport and maintain stable SV clusters.
Edwards SL, Morrison LM, Yorks RM, Hoover CM, Boominathan S, Miller KG. UNC-16 (JIP3) acts through synapse-assembly proteins to inhibit the active transport of cell soma organelles to Caenorhabditis elegans motor neuron axons. Genetics 201:117-141, 2015. [Abstract]
Edwards SL, Yorks RM, Morrison LM, Hoover CM, Miller KG. Synapse-assembly proteins maintain synaptic vesicle cluster stability and regulate synaptic vesicle transport in Caenorhabditis elegans. Genetics 201:91-116, 2015. [Abstract]
Hoover CM, Edwards SL, Yu SC, Kittelmann M, Richmond JE, Eimer S, Yorks RM, Miller KG. A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release from Caenorhabditis elegans Motor Neurons. Genetics 196:745-765, 2014. [Abstract] Featured article. See [Commentary] in same issue:196:601-604.
Edwards SL, Yu SC, Hoover CM, Phillips BC, Richmond JE, Miller KG. An Organelle Gatekeeper Function for Caenorhabditis elegans UNC-16 (JIP3) at the Axon Initial Segment. Genetics 194:143-161, 2013. [Abstract] Featured article. See [Commentary] in same issue.
Selected for [F1000Prime] and recommended as being of special significance in its field.
Edwards SL, Charlie NK, Richmond JE, Hegermann J, Eimer S, Miller KG. Impaired dense core vesicle maturation in Caenorhabditis elegans mutants lacking Rab2. J Cell Biol 186:881-895, 2009. [Abstract] Featured article. See In Focus in same issue: 186:769. [In Focus]
Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. A novel molecular solution for ultraviolet light detection in Caenorhabditis elegans. PLoS Biol 6:e198, 2008. [Abstract] Featured article. See Synopsis in same issue: [Synopsis]
Williams SL, Lutz S, Charlie NK, Vettel C, Ailion M, Coco C, Tesmer JJ, Jorgensen EM, Wieland T, Miller KG. Trio’s Rho-specific GEF domain is the missing Gαq effector in C. elegans. Genes Dev 21:2731-2746, 2007. [Abstract] Featured article. See journal commissioned Perspective. [Perspective]
Charlie NK, Schade MA, Thomure AM, Miller KG. Presynaptic UNC-31 (CAPS) is required to activate the Gαs pathway of the Caenorhabditis elegans synaptic signaling network. Genetics 172:943-961, 2006. [Abstract]
Reynolds NK, Schade MA, Miller KG. Convergent, RIC-8 – dependent Gα signaling pathways in the C. eleganssynaptic signaling network. Genetics 169:651-670, 2005. [Abstract]
Genetic Models of Disease Laboratory, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-1826
Fax: (405) 271-1827