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Free keywords:
Adaptor Proteins, Signal Transducing/*physiology
Animals
Cell Cycle Proteins/*physiology
Cells, Cultured
Dendritic Spines/*physiology
Embryo, Mammalian
Hippocampus/cytology
Humans
Luminescent Proteins/metabolism
Membrane Proteins/metabolism
Mutagenesis/physiology
Neurons/cytology
Oncogene Proteins/*physiology
Rats
Rats, Sprague-Dawley
Receptors, Eph Family/*physiology
Signal Transduction/*physiology
Synapses/*physiology
Time Factors
Transfection
Abstract:
Dendritic spines are small protrusions emerging from dendrites that receive excitatory input. The process of spine morphogenesis occurs both in the developing brain and during synaptic plasticity. Molecules regulating the cytoskeleton are involved in spine formation and maintenance. Here we show that reverse signaling by the transmembrane ligands for Eph receptors, ephrinBs, is required for correct spine morphogenesis. The molecular mechanism underlying this function of ephrinBs involves the SH2 and SH3 domain-containing adaptor protein Grb4 and the G protein-coupled receptor kinase-interacting protein (GIT) 1. Grb4 binds by its SH2 domain to Tyr392 in the synaptic localization domain of GIT1. Phosphorylation of Tyr392 and the recruitment of GIT1 to synapses are regulated by ephrinB activation. Disruption of this pathway in cultured rat hippocampal neurons impairs spine morphogenesis and synapse formation. We thus show an important role for ephrinB reverse signaling in spine formation and have mapped the downstream pathway involved in this process.
