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Published online December 1, 2008
doi:10.1083/jcb.200807188
The Journal of Cell Biology, Vol. 183, No. 5, 893-908
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Lee et al.
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Article

Synapses are regulated by the cytoplasmic tyrosine kinase Fer in a pathway mediated by p120catenin, Fer, SHP-2, and β-catenin



Seung-Hye Lee1, I.-Feng Peng2, Yu Gie Ng1, Masahiro Yanagisawa4, Shernaz X. Bamji1, Lisa P. Elia1, Janne Balsamo5, Jack Lilien5, Panos Z. Anastasiadis4, Erik M. Ullian1,2,3, and Louis F. Reichardt1,3

1 Department of Physiology, 2 Department of Ophthalmology, and 3 Neuroscience Program, University of California, San Francisco, San Francisco, CA 94158
4 Cell Adhesion and Metastasis, Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224
5 Department of Biological Sciences, University of Iowa, Iowa City, IA 52242

Correspondence to Seung-Hye Lee: Seung-Hye.Lee{at}ucsf.edu; or Louis F. Reichardt: Louis.Reichardt{at}ucsf.edu

Localization of presynaptic components to synaptic sites is critical for hippocampal synapse formation. Cell adhesion–regulated signaling is important for synaptic development and function, but little is known about differentiation of the presynaptic compartment. In this study, we describe a pathway that promotes presynaptic development involving p120catenin (p120ctn), the cytoplasmic tyrosine kinase Fer, the protein phosphatase SHP-2, and β-catenin. Presynaptic Fer depletion prevents localization of active zone constituents and synaptic vesicles and inhibits excitatory synapse formation and synaptic transmission. Depletion of p120ctn or SHP-2 similarly disrupts synaptic vesicle localization with active SHP-2, restoring synapse formation in the absence of Fer. Fer or SHP-2 depletion results in elevated tyrosine phosphorylation of β-catenin. β-Catenin overexpression restores normal synaptic vesicle localization in the absence of Fer or SHP-2. Our results indicate that a presynaptic signaling pathway through p120ctn, Fer, SHP-2, and β-catenin promotes excitatory synapse development and function.

S.X. Bamji's present address is Dept. of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.

L.P. Elia's present address is Elan Pharmaceuticals, Inc., South San Francisco, CA 94080.

Abbreviations used in this paper: CAZ, cytomatrix of active zone; DIV, day in vitro; EPSC, excitatory postsynaptic current; eEPSC, evoked EPSC; IP, immunoprecipitation; p120ctn, p120catenin; shRNA, small hairpin RNA; WT, wild type.

© 2008 Lee et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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