The molecular mechanisms mediating the development, innervation and stability of sensory axon- mechanoreceptor interactions are very poorly understood, yet they are likely to be important in human neuropathies associated with mechanoreceptor denervation and axon loss. Some human sensory neuropathies primarily affect large diameter sensory axons which preferentially innervate muscle and tendon mechanoreceptors (muscle spindle stretch receptors and Golgi tendon organs) to provide skeletal and muscle position sensation (proprioception) to the central nervous system. During prenatal skeletal muscle development, sensory axons regulate the expression of a specific repertoire of genes in contacted myotubes to mediate stretch receptor morphogenesis and stabilize their innervation. The specific molecular signals that predominate are unknown but identifying them is of considerable interest since proprioception deficits are a common and debilitating aspect of many sensory neuropathies. Without a better understanding of the molecular factors involved in establishing and maintaining innervation to muscle spindle stretch receptors, it will be difficult to formulate rational therapies to slow or reverse proprioceptive axon loss. The signal transduction pathways engaged in myotubes that are contacted by large diameter axons (la- afferents) and the molecular signals involved in maintaining sensory and motor innervation to them are very poorly understood;la-afferents provide instructive signals that transform a subpopulation of myotubes into spindle stretch receptors presumably by engaging gene regulatory networks that are specific for spindle morphogenesis. In previous work, we identified Egr3 as an essential transcriptional regulator of spindle development which is induced in myotubes by la-afferent innervation. This research plan is outlined in three specific aims: (i) to characterize the function of novel Egr3 regulated target genes in stretch receptor morphogenesis and innervation, (ii) to examine whether Egr3 mediated gene expression is sufficient to transform myotubes into intrafusal muscle fibers in the absence of la-afferent morphogenetic signaling and i) to determine whether Egr3 is necessary to fate specify myotubes to an intrafusal muscle fiber lineage. We anticipate that these studies will provide greater understanding of how sensory innervation controls muscle stretch receptor morphogenesis and will better define the role of Egr3 in regulating stretch receptor specific genes that may be involved in stabilizing sensory and motor innervation to them. Muscle and cutaneous thermo- and mechanoreceptors all depend upon sensory innervation for their morphogenesis suggesting that some common molecular mechanisms may be revealed by our studies focusing on nerve- muscle stretch receptor interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040748-08
Application #
7802916
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Porter, John D
Project Start
2001-03-19
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$314,916
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Fang, Feng; Marangoni, Roberta Goncalves; Zhou, Xingchun et al. (2016) Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor ?-Dependent Fibroblast Activation. Arthritis Rheumatol 68:1989-2002
Oliveira Fernandes, Michelle; Tourtellotte, Warren G (2015) Egr3-dependent muscle spindle stretch receptor intrafusal muscle fiber differentiation and fusimotor innervation homeostasis. J Neurosci 35:5566-78
Fang, Feng; Shangguan, Anna J; Kelly, Kathleen et al. (2013) Early growth response 3 (Egr-3) is induced by transforming growth factor-? and regulates fibrogenic responses. Am J Pathol 183:1197-1208
Quach, David H; Oliveira-Fernandes, Michelle; Gruner, Katherine A et al. (2013) A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation. J Neurosci 33:4570-83
Enjin, Anders; Leão, Katarina E; Mikulovic, Sanja et al. (2012) Sensorimotor function is modulated by the serotonin receptor 1d, a novel marker for gamma motor neurons. Mol Cell Neurosci 49:322-32
Li, Lin; Eldredge, Laurie C; Quach, David H et al. (2011) Egr3 dependent sympathetic target tissue innervation in the absence of neuron death. PLoS One 6:e25696
Eldredge, Laurie C; Gao, Xiaoguang M; Quach, David H et al. (2008) Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice. Development 135:2949-57
Gao, Xiaoguang; Daugherty, Rebecca L; Tourtellotte, Warren G (2007) Regulation of low affinity neurotrophin receptor (p75(NTR)) by early growth response (Egr) transcriptional regulators. Mol Cell Neurosci 36:501-14
Carter, John H; Lefebvre, Juliet M; Wiest, David L et al. (2007) Redundant role for early growth response transcriptional regulators in thymocyte differentiation and survival. J Immunol 178:6796-805
Carter, John H; Tourtellotte, Warren G (2007) Early growth response transcriptional regulators are dispensable for macrophage differentiation. J Immunol 178:3038-47

Showing the most recent 10 out of 13 publications