Synapses are regulated by the cytoplasmic tyrosine kinase Fer in a pathway mediated by p120catenin, Fer, SHP-2, and beta-catenin.
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 beta-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 beta-catenin. beta-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 beta-catenin promotes excitatory synapse development and function.
Lee
Seung-Hye
SH
Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA. Seung-Hye.Lee@ucsf.edu
Peng
I-Feng
IF
Ng
Yu Gie
YG
Yanagisawa
Masahiro
M
Bamji
Shernaz X
SX
Elia
Lisa P
LP
Balsamo
Janne
J
Lilien
Jack
J
Anastasiadis
Panos Z
PZ
Ullian
Erik M
EM
Reichardt
Louis F
LF
D000818:Animals; D001369:Axons / Q000201:enzymology; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000196:embryology / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000201:enzymology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission; D013997:Time Factors; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin
D051177:Catenins; D015815:Cell Adhesion Molecules; C495268:Ctnnb1 protein, rat; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051176:beta Catenin; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin; C000722355:Ctnnd1 protein, rat