Dr. Lin obtained his Ph.D. in Neurobiology from the State University of New York at Albany in 1996. He then moved to the Salk Institute at La Jolla, Calif., as a postdoctoral fellow and research associate. He joined the faculty at the Department of Neuroscience in 2003.
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 adulthood. Toward this goal, we are currently focusing on the following two areas of research.
Patterning and Formation of Synapses
Formation of synapses lays the foundation for neural circuits. We study the vertebrate neuromuscular junction (NMJ) to understand the cellular and molecular mechanisms of synaptogenesis. 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. One of the questions that we are particularly interested in is to identify signaling molecules that determine the spatial pattern of synaptic organization of the NMJ. We are investigating a number of mutant mice in which the NMJ pattern is disrupted due to a specific mutations. This will allow us to define the roles of specific molecules in determining the patterning and formation of synapses.
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 are studying these transgenic mice in order to gain a better understanding of mechanisms underlying synaptic dysfunction and degeneration.
Yun Liu, Hongqiao Li, Yoshie Sugiura, Gilbert Gallardo, Mikhail Khvotchev, Weiping Han, Thomas C. Südhof and Weichun Lin (2015) Ubiquitin-Synaptobrevin fusion protein causes degeneration of presynaptic motor terminals in mice. Journal of Neuroscience 35 (33):11514-11531. PMID: 26290230
Choi HY, Liu Y, Tennert C, Sugiura Y, Karakatsani A, Kröger S, Johnson EB, Hammer RE, Lin W, Herz J. APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. Elife. 2013 Aug 20;2:e00220. doi: 10.7554/eLife.00220. PubMed PMID: 23986861.
Yun Liu, Yoshie Sugiura, Fenfen Wu, Wentao Mi, Makoto M. Taketo, Steve Cannon, Thomas Carroll and Weichun Lin (2012) β-Catenin stabilization in skeletal muscles, but not in motor neurons, leads to aberrant motor innervation of the muscle during neuromuscular development in mice. Developmental Biology, 366:255-267. PMID: 22537499
Fujun Chen, Yun Liu, Yoshie Sugiura, Paul D. Allen, Ronald G. Gregg and Weichun Lin (2011) Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors. Nat Neurosci. 14(5):570-7.
Yun Liu, Yoshie Sugiura and Weichun Lin (2011) The role of Synaptobrevin-1/VAMP-1 in Ca2 -triggered synaptic transmission at the mouse NMJ. J Physiol. 589:1603-18.
Mahru An, Weichun Lin, Jiefei Yang, Bertha Dominguez, Daniel Padgett, Yoshie Sugiura, Prafulla Aryal, Thomas W. Gould, Ronald W. Oppenheim, Mark Hester, Brian Kasper, Chien-Ping Ko and Kuo-Fen Lee (2010) Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. Proceedings of the National Academy of Sciences, U.S.A. 107:10702-7.
Fujun Chen, Yoshie Sugiura, Kalisa Galina Myers, Yun Liu, and Weichun Lin (2010) Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction. Proceedings of the National Academy of Sciences, U.S.A. 107:1636-1641.
Yun Liu, Yoshie Sugiura, Daniel Padgett and Weichun Lin (2010) Post-synaptic development of the neuromuscular junction in mice lacking the gamma-subunit of muscle nicotinic acetylcholine receptor. Journal of Molecular Neuroscience, 40: 21-26.
Yun Liu, Oppenheim, R. W., Sugiura, Y., and Weichun Lin (2009) Abnormal development of the neuromuscular junction in Nedd4-deficient mice. Developmental Biology, 330:153-166.
Yun Liu, Daniel Padgett, Masazumi Takahashi, Hongqiao Li, Ayaz Sayeed, Russell W. Teichert, Baldomero M. Olivera, Joseph McArdle, William N. Green, and Weichun Lin (2008) Essential roles of acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning. Development, 135:1957-1967.
Zhiping Pang, Ernestina Melicoff, Daniel Padgett, Yun Liu, Andrew F. Teich, Burton F. Dickey, Weichun Lin, Roberto Adachi, and Thomas Sudhof (2006) Synaptotagmin-2 is essential for survival and contributes to Ca2 triggering of neurotransmitter release in central and neuromuscular synapses. Journal of Neuroscience, 26:13493-13504.
Susanne Schoch, Tobias Mittelstaedt, Pascal S. Kaeser, Daniel Padgett, Nicole Feldmann, Vivien Cgeveleyre, Pablo E. Cassillo, Robert Hammer, Weiping Han, Frank Schmitz, Weichun Lin, and Thomas Sudhof (2006) Redundant functions of RIM1-alpha and RIM2-alpha in Calcium triggered neurotransmitter release. EMBO Journal, 25:5852-5863.
Weiping Han, Jeong-Seop Rhee, Anton Maximov, Weichun Lin, Robert Hammer, Christian Rosenmund and Thomas Sudhof (2005) C-terminal ECFP fusion impairs synaptotagmin-1 function: crowding out synaptotagmin1. J Biol Chem, 280:5089-5100.
Weichun Lin, Bertha Dominguez, Jiefei Yang, Prafulla Aryal, Eugene P. Brandon, Fred H. Gage and Kuo-Fen Lee (2005) Neurotransmitter acetylcholine negatively regulates. Neuromuscular synapse formation through a Cdk5-dependent mechanism. Neuron, 46:569-579.
Eugene P. Brandon*, Weichun Lin*, Kevin A. D'Amour, Donald P. Pizzo, Bertha Dominguez, Yoshie Sugiura, Sile Thode, Chien-Ping Ko, Leon J. Thal, Fred H. Gage and Kuo-Fen Lee (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase deficient mice. Journal of Neuroscience 23:539-549 *Co-first author
Weichun Lin, Robert Burgess, Bertha Dominguez, Samuel Pfaff, Joshua Sanes and Kuo-Fen Lee (2001) Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature, 410:1057-1064.
Weichun Lin, Hugo Sanchez, Tom Deerinck, Jacqueline K. Morris, Mark Ellisam and Kuo-Fen Lee (2000) Abnormal development of motor axons and neuromuscular synapses in erbB2-deficient mice. Proceedings of the National Academy of Sciences, 97:1299-1304.
Jacqueline K. Morris*, Weichun Lin*, Chris Hauser, Yelena Marchuk, Damon Getman, and Kuo-Fen Lee (1999) Rescue of cardiac defect in erbB2 null mutant mice reveals essential roles of erbB2 in peripheral nervous system development. Neuron, 23:273-283. *Co-first author.