Overview
The mammalian motor system makes constant short- and long-term adaptations in response to varying demands. My laboratory takes a comprehensive approach to the investigation of the plasticity and maintenance of the neuromuscular system. We combine molecular genetic techniques with sensitive functional and structural assays to study a variety of mouse models of neuromuscular disease that affect different components of the system. For example, in collaboration with Dr. Gregory Cox we recently helped characterize a novel muscular dystrophy and are seeking to identify genetic modifiers of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). We are also working on a series of studies to investigate the role of cholinergic transmission of motor neurons in maintaining neuromuscular function in adult mice.
Research details
Plasticity and Maintenance of the Adult Motor System
Overview
The mammalian motor system makes constant short- and long-term adaptations in response to varying demands. Changes occur at all levels of the system but converge upon the "final common pathway," the alpha motor neuron in the spinal cord, which innervates the skeletal muscles. Mammalian motor neurons vary in the number of muscle fibers they innervate to form motor units that differ in size and functional characteristics. This design principle allows the nervous system to transduce neural activity into smooth, forceful, coordinated movement. Accurate transduction of output signals depends, in part, on the anatomical and functional stability of individual motor units. The coordinated properties of individual motor units are, in turn, dependent upon ongoing dynamic processes that require communication between (at least) the motor neuron, the muscle fibers it innervates, and associated Schwann cells. Our knowledge of the identity, sources and regulation of the molecular signals involved in this communication is incomplete.
My laboratory takes a comprehensive approach to the study of the plasticity and maintenance of the neuromuscular system. In collaboration with the laboratories of Drs. Gregory Cox and Robert Burgess at The Jackson Laboratory, we combine molecular genetic techniques with sensitive functional and structural assays. Functional characterization extends from the level of the whole animal, using an automated gait analysis system we developed (Wooley et al., 2005), to classic in situ and in vitro electrophysiological measures of muscle contractile properties and synaptic function.
Disease models
We study a variety of mouse models of neuromuscular disease that affect different components of the system. For example, in ongoing collaboration with the Cox laboratory, we have recently contributed to the description of a novel muscular dystrophy. The mdm mice (Huebsch et al., 2005) carry a recessive mutation in the gene that codes for the giant structural protein titin that causes early onset muscular dystrophy. Our findings from analysis of gait in mdm heterozygotes suggest a possible signaling role for the mutated portion of the protein in controlling muscle contraction during normal gait.
In other work, collaborating with the Burgess laboratory, we used a mouse that presented with a peripheral neuropathy to identify a dominant point mutation in the gene Gars [encoding glycyl-tRNA synthetase (GlyRS)]. This work led to the description of the first mouse model of the human Charcot-Marie-Tooth type 2D (Seburn et al., 2006). The mutated GlyRS takes on a novel pathogenic function and causes the breakdown of neuromuscular connections and ultimately the loss of motor and sensory axons. Our initial report provided insights not available from studies in humans and ongoing work should further improve our understanding of this human disease.
A third area of ongoing research is aimed at finding genetic modifiers of the disease amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) induced by mutations in the superoxide dismutase 1 gene (Sod1). In collaboration with Dr. Cox, we have found QTLs in different inbred strains of mice that modify the onset of the SOD1-induced disease. In future experiments, we hope to narrow the QTL regions and then confirm the identity and test the potency of these regions by moving identified QTLs between strains with the ultimate goal of fine mapping the underlying genetic differences responsible for modifying the disease.
Targeted mutations in normal mice
We also use targeted genetic manipulations to study key components of the motor system. A series of studies currently underway will investigate the role of cholinergic transmission of motor neurons in maintaining neuromuscular function in adult mice. A novel model of genetic "partial denervation" will be used to examine, within a specified motor pool, the response of normal motor units to the presence of "silent" intact motor units. This approach offers advantages over the use of surgical or pharmacological methods that either remove the physical connection or eliminate evoked release but not spontaneous release. In this inducible knockout model (Chattm1.1Jrs), choline actelytransferase expression is eliminated, thereby stopping acetylcholine production and removing all cholinergic communication between a subset of motor neurons and their postsynaptic targets. The ACh-mediated nerve-muscle communication provided by spontaneous transmitter release is important for the developing system and in synapse-glial communication of adults, but its long-term role in maintenance is not yet clear. Future studies will exploit the ChAT mouse to investigate the effects of progressive and long-term silencing of cholinergic communication.
Lab staff
Principal Investigator: Kevin Seburn, Ph.D.
Laboratory Technician IV: Christine Rosales, B.S.
Publication listings
Zhou X, Jen PHS, Seburn KL, Frankel WN, Zheng QY. 2006 Auditory brain stem responses in 10 inbred strains of mice. Brain Res May 26;1091(1):16-26
Wang Y, Seburn K, Bechtel L, Lee BY, Szatkiewicz JP, Nishina PM, Naggert JK. 2006 Defective carbohydrate metabolism in mice homozygous for tubby mutation. Physiol Genomics Oct 11;27(3):131-40.
Traka M, Seburn KL, Popko B. 2006 Nmf11 is a novel ENU-induced mutation in the mouse glycine receptor alpha 1 subunit. Mamm Genome Sept 17(9):950-955.
Seburn KL, Nangle LA, Cox GA, Schimmel P. Burgess RW. 2006. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron Sept 21 51(6):715-26.
Runkel F, Bussow H, Seburn KL, Cox GA, Ward DM, Kaplan J, Franz T. 2006 Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25. Mamm Genome March;17(3):203-10.
Wooley CM, Sher RB, Kale A, Frankel WN, Cox GA, Seburn KL. 2005 Gait analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve 32(1):43-50.
Huebsch KA, Kudryashova E, Wooley CM, Sher RB, Seburn KL, Spencer MJ, Cox GA. 2005 Mdm muscular dystrophy: interactions with calpain 3 and a novel functional role for titin's N2A domain. Hum Mol Genet 14(19):2801-2811.
Concepcion D, Seburn KL, Wen G, Frankel WN, Hamilton BA 2004 Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice. Genetics 168(2):953-959.
Buchner DA, Seburn KL, Frankel WN, Meisler MH. 2004. Three ENU-induced neurological mutants in the pore loop of sodium channel Scn8a (Na(v)1.6) and a genetically linked retinal mutation, rd13. Mamm Genome 15(5):344-351.
Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL 2002 The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature Sept 26;419(6905)367-74.
Ward S, Seburn K, Galante RJ, Pack Al. 2002 Non-invasive phenotyping of sleep in mice. Sleep (24(suppl.))A410.
