The human brain contains over 100 billion neurons inter-connected through specialized cell-cell contacts termed synapses. Synaptic connections, estimated to be around 100 trillion in number, form intricate networks that enable neurons to send and receive information, and to generate complex behavior. The goal of our research is to understand how neurons establish synaptic connections during development, and how these connections are maintained throughout life. Toward this goal, we are currently focusing on the following two areas of research.
I. Patterning and formation of synapses Formation of synapses is a fundamental process that lays the foundation for neural circuits. We chose the vertebrate neuromuscular junction (NMJ) as our model system to study synapse formation. At the developing NMJ, the nerve terminals progressively accumulate synaptic proteins, and form synapses within a discrete area often localized to the central region of the muscle. It is not clear what determines such a spatial pattern of synaptic organization. We analyze a number of mutant mice in which normal synaptic connections are disrupted in order to understand the underlying mechanisms. Our approach combines electrophysiology, molecular biology and mouse genetics.
II. Molecular mechanisms of neurodegeneration Impairments of synapses are implicated in the pathogeneses of various neurodegenerative diseases, including Alzheimer’s disease and amyotrophic lateral sclerosis ( Lou Gehrig’s disease). Indeed, synaptic dysfunction may be the earliest sign of neurodegeneration, but little is known why normal synapses may degenerate. We have generated a transgenic mouse model in which synapses form normally during development, but become progressively dysfunctional and eventually degenerate. We study these transgenic mice in order to gain a better understanding of mechanisms underlying synaptic dysfunction and degeneration.
RESEARCH INTERESTS
Synapse formation
Neurodegeneration
RECENT PUBLICATIONS
Weichun Lin, Hugo Sanchez, Tom Deerinck, Jacqueline K. Morris, Mark Ellisam and Kuo-Fen Lee, "Abnormal development of motor axons and neuromuscular synapses in erbB2-deficient mice." Proceedings of the National Academy of Sciences, U.S.A, 97:1299-1304, 2000
Weichun Lin, Robert Burgess, Bertha Dominguez, Samuel Pfaff, Joshua Sanes and Kuo-Fen Lee, "Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse." Nature, 410:1057-1064, March 2001
Eugene P. Brandon*, Weichun Lin*, Kevin A. D?Amour, Donald P. Pizzo, Bertha Dominguez, Yoshie Sugiura, Silke Thode, Chien-Ping Ko, Leon J. Thal, Fred H. Gage and Kuo-Fen Lee, "Aberrant patterning of neuromuscular synapses in choline acetyltransferase deficient mice." Journal of Neuroscience, 23:539-549, January 2003
Weichun Lin, Bertha Dominguez, Jiefei Yang, Prafulla Aryal, Eugene P. Brandon, Fred H. Gage and Kuo-Fen Lee, "Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism." Neuron, 46:569-579, May 2005
Yun Liu, Daniel Padgett, Masazumi Takahashi, Hongqiao Li, Ayaz Sayeed, Russell W. Teichert, Baldomero M. Olivera, Joseph McArdle, William N. Green, and Weichun Lin, "Essential roles of acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning" Development, 135:1957-1967, June 2008
SIGNIFICANT PUBLICATIONS
Weichun Lin, Robert Burgess, Bertha Dominguez, Samuel Pfaff, Joshua Sanes and Kuo-Fen Lee, "Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse." Nature, 410:1057-1064, March 2001
Yun Liu, Daniel Padgett, Masazumi Takahashi, Hongqiao Li, Ayaz Sayeed, Russell W. Teichert, Baldomero M. Olivera, Joseph McArdle, William N. Green, and Weichun Lin, "Essential roles of acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning" Development, 135:1957-1967, June 2008
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