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J. Biol. Chem., Vol. 281, Issue 3, 1587-1598, January 20, 2006

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EphB Receptors Regulate Dendritic Spine Morphogenesis through the Recruitment/Phosphorylation of Focal Adhesion Kinase and RhoA Activation^*

Michael L. Moeller, Yang Shi, Louis F. Reichardt1, and Iryna M. Ethell2

From the Division of Biomedical Sciences, University of California Riverside, Riverside, California 92521 and the Howard Hughes Medical Institute and Department of Physiology, University of California San Francisco, San Francisco, California 94143

Dendritic filopodia are small protrusions on the surface of neuronal dendrites that transform into dendritic spines upon synaptic contact with axon terminals. The formation of dendritic spines is a critical aspect of synaptic development. Dendritic spine morphogenesis is characterized by filopodia shortening followed by the formation of mature mushroom-shaped spines. Here we show that activation of the EphB receptor tyrosine kinases in cultured hippocampal neurons by their ephrinB ligands induces morphogenesis of dendritic filopodia into dendritic spines. This appears to occur through assembly of an EphB-associated protein complex that includes focal adhesion kinase (FAK), Src, Grb2, and paxillin and the subsequent activations of FAK, Src, paxillin, and RhoA. Furthermore, Cre-mediated knock-out of loxP-flanked fak or RhoA inhibition blocks EphB-mediated morphogenesis of dendritic filopodia. Finally, EphB-mediated RhoA activation is disrupted by FAK knock-down. These data suggest that EphB receptors are upstream regulators of FAK in dendritic filopodia and that FAK-mediated RhoA activation contributes to assembly of actin filaments in dendritic spines.

Received for publication, October 31, 2005 , and in revised form, November 17, 2005.

^* This work is supported by National Institutes of Health Grants MH67121 (to I. M. E.) and NS19090 (to L. F. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ An Investigator of the Howard Hughes Medical Institute.

² To whom correspondence should be addressed: Division of Biomedical Sciences, University of California Riverside, B601 Statistics Rd., Riverside, CA 92521. Tel.: 951-827-2186; Fax: 951-827-7121; E-mail: iryna.ethell{at}ucr.edu.

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