The patterning and formation of synapses is fundamental to nervous system function. The long-term objective of our research is to understand the cellular and molecular mechanisms underlying the formation of synapse, using the vertebrate neuromuscular junction (NMJ) as our model. During the initial stages of neuromuscular synaptogenesis, nascent AChRs are clustered preferentially in the central region of the muscle. The presence of these AChR clusters coincides with the arrival of the nerves, but the majority of these clusters are not directly contacted by the ingrowing nerves;subsequent development leads to Formation of juxtaposed apposition between the pre-synaptic nerve terminal and the post-synaptic AChR. These nerve-independent initial AChRs are termed muscle prepatterning. A critical question that remains unanswered is whether the prepatterning of postsynaptic proteins such as AChRs contributes in any way to the formation of the NMJs. We hypothesize that these fetal AChRs are essential for defining the normal innervation boundaries critical for the establishment of initial neuromuscular synaptic pattern. This hypothesis will be tested by two independent, but complementary, approaches: 1) in mutant mice deficient in the AChR y-subunit gene, and 2) in mouse embryos treated with conotoxins that specifically recognize and block fetal AChRs. We will examine the formation of synaptic patterns in the absence of the initial AChR clustering to determine the extent that fetal AChRs contribute to pre-synaptic differentiation and pattern formation. Furthermore, using electrophysiology, we will characterize synaptic transmission in the developing NMJ in the absence of the y-subunit. Using conotoxins to block the fetal AChRs, we will determine whether the function of postsynaptic AChRs is essential for the formation of the NMJ. This proposed project will provide a better understanding of the mechanisms underlying synapse formation. In addition, since AChR deficiency is implicated in neuromuscular disorders such as myasthenia gravis (MG) and congenital myasthenic syndromes (CMSs), this proposed project will also provide a basis for better understanding the pathogeneses of these neuromuscular diseases. Furthermore, increasing evidence shows that distal axonal or neuromuscular synaptic dysfunction occurs prior to the degeneration of motoneurons in diseases such as amyotrophic lateral sclerosis (ALS). Therefore, elucidating mechanisms underlying the structural and functional changes of the pre-synaptic nerves at the NMJ will also provide insight towards a better understanding of motoneuron diseases and may provide new targets for therapeutic intervention for motoneuron diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055028-03
Application #
7576903
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Talley, Edmund M
Project Start
2007-05-15
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$343,438
Indirect Cost
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
Anderson, Douglas M; Cannavino, Jessica; Li, Hui et al. (2016) Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106. Proc Natl Acad Sci U S A 113:E4494-503
Liu, Yun; Li, Hongqiao; Sugiura, Yoshie et al. (2015) Ubiquitin-Synaptobrevin Fusion Protein Causes Degeneration of Presynaptic Motor Terminals in Mice. J Neurosci 35:11514-31
May-Simera, Helen L; Petralia, Ronald S; Montcouquiol, Mireille et al. (2015) Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea. Development 142:555-66
Nelson, Benjamin R; Wu, Fenfen; Liu, Yun et al. (2013) Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proc Natl Acad Sci U S A 110:11881-6
Choi, Hong Y; Liu, Yun; Tennert, Christian et al. (2013) APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. Elife 2:e00220
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
Sugiura, Yoshie; Lin, Weichun (2011) Neuron-glia interactions: the roles of Schwann cells in neuromuscular synapse formation and function. Biosci Rep 31:295-302
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
Sugiura, Yoshie; Chen, Fujun; Liu, Yun et al. (2011) Electrophysiological characterization of neuromuscular synaptic dysfunction in mice. Methods Mol Biol 793:391-400

Showing the most recent 10 out of 15 publications