The long-term goal of our research project is to define mechanisms involved in regulating the formation, maintenance, and maturation of pre- and postsynaptic elements of the neuromuscular junction (NMJ). The NMJ is the chemical synaptic connection between motor neuron and skeletal muscle;it is essential for routine activities such as breathing, swallowing, and movement. We selected the NMJ as a model because it can provide information pertinent to both peripheral and central synapses, while its relatively simple structure and easy accessibility make it more amenable to investigation than the central synapse. This project addresses a fundamental question in the interaction between the pre- and postsynaptic elements of the NMJ - how muscle talks to nerve to establish and maintain normal NMJ patterns. Using genetic models in mice, we found that the dihydropyridine receptor (DHPR) - which is known for its role in muscle contraction - plays a crucial regulatory role in the development of innervation pattern and differentiation of motor neurons and motor nerve terminals. This finding was unexpected, in part because much of the information known about the regulation of the pre-synaptic development point to a predominantly "neurocentric paradigm." The discovery of an important muscle-derived regulator suggests that muscle plays a much more active role in regulating presynaptic elements than was previously believed. Our findings provide a new avenue of investigation for identifying feedback mechanisms from muscle to nerve. We hypothesize that DHPRs in skeletal muscle regulate the differentiation of pre-synaptic nerve terminals and the survival of motor neurons in a retrograde fashion through its influence on the expression of muscle-specific genes. We plan to use a multidisciplinary approach to test this hypothesis and to elucidate the molecular mechanisms responsible for this regulatory activity. By identifying these regulatory signals, we may be able to provide additional targets for the development of therapeutic strategies to cure, control, or prevent neurodevelopmental disorders and neurodegenerative diseases.

Public Health Relevance

This project aims at defining mechanisms responsible for regulating the formation and maintenance of the NMJ. This is important because abnormal formation or function of the NMJ is implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Therefore, identifying regulatory mechanisms responsible for structural and functional changes in the NMJ will enable us to improve current treatment strategies for neurodegenerative diseases such as ALS and SMA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055028-07
Application #
8467064
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Gubitz, Amelie
Project Start
2006-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$335,639
Indirect Cost
$124,545
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Liu, Yun; Sugiura, Yoshie; Wu, Fenfen et al. (2012) ýý-Catenin stabilization in skeletal muscles, but not in motor neurons, leads to aberrant motor innervation of the muscle during neuromuscular development in mice. Dev Biol 366:255-67
Liu, Yun; Sugiura, Yoshie; Lin, Weichun (2011) The role of synaptobrevin1/VAMP1 in Ca2+-triggered neurotransmitter release at the mouse neuromuscular junction. J Physiol 589:1603-18
Chen, Fujun; Liu, Yun; Sugiura, Yoshie et al. (2011) Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors. Nat Neurosci 14:570-7
Liu, Yun; Sugiura, Yoshie; Padgett, Daniel et al. (2010) Postsynaptic development of the neuromuscular junction in mice lacking the gamma-subunit of muscle nicotinic acetylcholine receptor. J Mol Neurosci 40:21-6
An, Mahru C; Lin, Weichun; Yang, Jiefei et al. (2010) Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. Proc Natl Acad Sci U S A 107:10702-7
Chen, Fujun; Sugiura, Yoshie; Myers, Kalisa Galina et al. (2010) Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction. Proc Natl Acad Sci U S A 107:1636-41
Liu, Yun; Oppenheim, Ronald W; Sugiura, Yoshie et al. (2009) Abnormal development of the neuromuscular junction in Nedd4-deficient mice. Dev Biol 330:153-66
Liu, Yun; Padgett, Daniel; Takahashi, Masazumi et al. (2008) Essential roles of the acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning. Development 135:1957-67