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The Journal of Neuroscience, December 19, 2007, 27(51):14205-14215; doi:10.1523/JNEUROSCI.2746-07.2007

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Development/Plasticity/Repair
The EphA4 Receptor Regulates Neuronal Morphology through SPAR-Mediated Inactivation of Rap GTPases

Melanie Richter,¹ Keith K. Murai,^2 * Caroline Bourgin,^1 * Daniel T. Pak,³ and Elena B. Pasquale^1,4

¹Burnham Institute for Medical Research, La Jolla, California 92037, ²Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada H3G 1A4, ³Department of Pharmacology, Georgetown University Medical School, Washington, DC 20007, and ⁴Pathology Department, University of California San Diego, La Jolla, California 92093

Correspondence should be addressed to Elena B. Pasquale, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: elenap{at}burnham.org

Eph receptors play critical roles in the establishment and remodeling of neuronal connections, but the signaling pathways involved are not fully understood. We have identified a novel interaction between the C terminus of the EphA4 receptor and the PDZ domain of the GTPase-activating protein spine-associated RapGAP (SPAR). In neuronal cells, this binding mediates EphA4-dependent inactivation of the closely related GTPases Rap1 and Rap2, which have recently been implicated in the regulation of dendritic spine morphology and synaptic plasticity. We show that SPAR-mediated inactivation of Rap1, but not Rap2, is critical for ephrin-A-dependent growth cone collapse in hippocampal neurons and decreased integrin-mediated adhesion in neuronal cells. Distinctive effects of constitutively active Rap1 and Rap2 on the morphology of growth cones and dendritic spines support the idea that these two GTPases have different functions in neurons. Together, our data implicate SPAR as an important signaling intermediate that links the EphA4 receptor with Rap GTPase function in the regulation of neuronal morphology.

Key words: growth cone collapse; dendritic spine; hippocampus; ephrin; integrin; tyrosine kinase

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Received June 16, 2007; revised Sept. 28, 2007; accepted Nov. 1, 2007.

Correspondence should be addressed to Elena B. Pasquale, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: elenap{at}burnham.org

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