The neuregulins (NRGs) are a family of neuronally-derived growth and differentiation factors that 'target" the axoglial interface and neuromuscular junctions (NMJs) through both soluble, heparin-binding and membrane anchored alternatively spliced forms. They promote proliferation, migration, survival, and myelination of both peripheral and central glia. At the NMJ, their role is less clear, but heparin-binding forms accumulate within the basal lamina of NMJs at distinct developmental stages and induce acetylcholine receptors, suggesting that they promote synaptic strength. Given the close proximity of the axon to both muscle and Schwann cell targets, the direct and indirect effects of NRG1 on muscle and nerve have been difficult to establish. Our laboratory focuses on the soluble, heparin-binding forms of NRG1. We found that soluble forms of NRG1 are rapidly released from both sensory and motor neuron axons in response to Schwann cell and muscle-derived neurotrophic factors such as BDNF and GDNF, and that this pathway is regulated by protein kinase C. Once released, NRG1 becomes concentrated within the nerve and at NMJs through highly specific interactions with heparan sulfate proteoglycans (HSPGs). Here, we will explore how NRG1 promotes peripheral nerve and NMJ development in both chick and mouse embryos through two sequential mechanisms. (1) Regulated release from axons by Schwann cell and muscle-derived neurotrophic factors, (2) Neurotrophic factor-induced PKC signaling. Once released from axons, NRG1 will be localized to sites where it accumulates in the extracellular matrix through developmentally-expressed heparan-sulfate proteoglycans (HSPGs). In an important part of these studies, we will also test a novel therapeutic method to target biological therapeutics to axoglial and neuromuscular junctions using NRG1's heparin-binding domain as a specific targeting motif. Relevance: To date there are few effective treatments for diseases of the peripheral and central nervous systems. A promising means to overcome this is to develop biologically-driven therapeutics that use growth factors required for nervous system formation. This proposal will attempt to overcome some off the major limitations in developing such therapeutics through an improved understanding of normal development and improved ways to target novel therapeutics within the nervous system.

Public Health Relevance

Understanding the mechanisms that regulate the release and localization of neuregulin at the peripheral nerve and neuromuscular junction will be critical to design effective therapeutics for diseases of peripheral nerve and neuromuscular disorders, such as neuropathy andALS,aswellasCNSdisorders,suchasmultiplesclerosisandschizophrenia.Treatmentscould consist of promoting neuregulin or neurotrophin signaling, and/or promoting neuregulin release through activation of PKC-4 signaling. Our studies also test a more general 'targeting'system we invented that effectively delivers therapeutics to specific cell types through their unique heparan sulfate composition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059947-03
Application #
8220869
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Gubitz, Amelie
Project Start
2010-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
Wayne State University
Department
Neurology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Song, Fei; Chiang, Pohung; Ravits, John et al. (2014) Activation of microglial neuregulin1 signaling in the corticospinal tracts of ALS patients with upper motor neuron signs. Amyotroph Lateral Scler Frontotemporal Degener 15:77-83
Jeng, David; Ma, Zhenzhong; Barrett, John W et al. (2013) The tanapoxvirus 15L protein is a virus-encoded neuregulin that promotes viral replication in human endothelial cells. J Virol 87:3018-26
Song, Fei; Bandara, Manoj; Deol, Harvinder et al. (2013) Complexity of trophic factor signaling in experimental autoimmune encephalomyelitis: differential expression of neurotrophic and gliotrophic factors. J Neuroimmunol 262:11-8
Song, Fei; Chiang, Pohung; Wang, Jiajing et al. (2012) Aberrant neuregulin 1 signaling in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 71:104-15
Ma, Zhenzhong; Wang, Jiajing; Song, Fei et al. (2011) Critical period of axoglial signaling between neuregulin-1 and brain-derived neurotrophic factor required for early Schwann cell survival and differentiation. J Neurosci 31:9630-40