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Published online September 17, 2007
doi:10.1083/jcb.200610139
The Journal of Cell Biology, Vol. 178, No. 7, 1295-1307
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Bourgin et al.
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Article

 The EphA4 receptor regulates dendritic spine remodeling by affecting ß1-integrin signaling pathways

Caroline Bourgin1, Keith K. Murai2, Melanie Richter1, and Elena B. Pasquale1,3

1 Burnham Institute for Medical Research, La Jolla, CA 92037
2 Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, McGill University Health Centre, Montreal General Hospital, Quebec H3G 1A4, Canada
3 Pathology Department, University of California, San Diego, La Jolla, CA 92093

Correspondence to Elena B. Pasquale: elenap{at}burnham.org

Remodeling of dendritic spines is believed to modulate the function of excitatory synapses. We previously reported that the EphA4 receptor tyrosine kinase regulates spine morphology in hippocampal pyramidal neurons, but the signaling pathways involved were not characterized (Murai, K.K., L.N. Nguyen, F. Irie, Y. Yamaguchi, and E.B. Pasquale. 2003. Nat. Neurosci. 6:153–160). In this study, we show that EphA4 activation by ephrin-A3 in hippocampal slices inhibits integrin downstream signaling pathways. EphA4 activation decreases tyrosine phosphorylation of the scaffolding protein Crk-associated substrate (Cas) and the tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) and also reduces the association of Cas with the Src family kinase Fyn and the adaptor Crk. Consistent with this, EphA4 inhibits ß1-integrin activity in neuronal cells. Supporting a functional role for ß1 integrin and Cas inactivation downstream of EphA4, the inhibition of integrin or Cas function induces spine morphological changes similar to those associated with EphA4 activation. Furthermore, preventing ß1-integrin inactivation blocks the effects of EphA4 on spines. Our results support a model in which EphA4 interferes with integrin signaling pathways that stabilize dendritic spines, thus modulating synaptic interactions with the extracellular environment.

Abbreviations used in this paper: ANOVA, analysis of variance; Cas, Crk- associated substrate; EGFP-F, farnesylated enhanced GFP; FAK, focal adhesion kinase; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate; PSD, postsynaptic density; Pyk2, proline-rich tyrosine kinase 2.


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