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

J Cell Biol. 2008 Dec 1;183(5):893-908. doi: 10.1083/jcb.200807188.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / enzymology
  • Catenins
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • Cytoplasm / enzymology
  • Excitatory Postsynaptic Potentials
  • Hippocampus / embryology
  • Hippocampus / enzymology*
  • Neurons / enzymology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Presynaptic Terminals / enzymology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Synaptic Transmission*
  • Time Factors
  • Transfection
  • beta Catenin / genetics
  • beta Catenin / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Catenins
  • Cell Adhesion Molecules
  • Ctnnb1 protein, rat
  • Phosphoproteins
  • RNA, Small Interfering
  • beta Catenin
  • delta catenin
  • proto-oncogene protein c-fes-fps
  • Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • rhoA GTP-Binding Protein