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J. Biol. Chem., Vol. 281, Issue 28, 19358-19368, July 14, 2006

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Versican G3 Domain Regulates Neurite Growth and Synaptic Transmission of Hippocampal Neurons by Activation of Epidermal Growth Factor Receptor^*

Yun-Yan Xiang¹, Haiheng Dong¹, Yudi Wan, Jingxin Li, Albert Yee, Burton B. Yang^¶23, and Wei-Yang Lu^||24

From the Sunnybrook Health Sciences Centre and the Departments of Anesthesia, ^||Physiology, and ^¶Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M4N 3M5, Canada

Versican is one of the major extracellular matrix (ECM) proteins in the brain. ECM molecules and their cleavage products critically regulate the growth and arborization of neurites, hence adjusting the formation of neural networks. Recent findings have revealed that peptide fragments containing the versican C terminus (G3 domain) are present in human brain astrocytoma. The present study demonstrated that a versican G3 domain enhanced cell attachment, neurite growth, and glutamate receptor-mediated currents in cultured embryonic hippocampal neurons. In addition, the G3 domain intensified dendritic spines, increased the clustering of both synaptophysin and the glutamate receptor subunit GluR2, and augmented excitatory synaptic activity. In contrast, a mutated G3 domain lacking the epidermal growth factor (EGF)-like repeats (G3EGF) had little effect on neurite growth and glutamatergic function. Treating the neurons with the G3-conditioned medium rapidly increased the levels of phosphorylated EGF receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase (pERK), indicating an activation of EGFR-mediated signaling pathways. Blockade of EGFR prevented the G3-induced ERK activation and suppressed the G3-provoked enhancement of neurite growth and glutamatergic function but failed to block the G3-mediated enhancement of cell attachment. These combined results indicate that the versican G3 domain regulates neuronal attachment, neurite outgrowth, and synaptic function of hippocampal neurons via EGFR-dependent and -independent signaling pathway(s). Our findings suggest a role for ECM proteolytic products in neural development and regeneration.

Received for publication, December 5, 2005 , and in revised form, March 21, 2006.

^* This work was supported by grants from the Canadian Institutes of Health Research and the Canadian Neurotrauma Research Program (to W.-Y. L.) and J. P. Bickell (to W.-Y. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² Canadian Institutes of Health Research New Investigators.

³ To whom correspondence may be addressed: Research Building, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada. Tel.: 416-480-5874; Fax: 416-480-5737; E-mail: burton.yang{at}sri.utoronto.ca.

⁴ To whom correspondence may be addressed: Research Building, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada. Tel.: 416-480-4823; Fax: 416-480-5737; E-mail: wlu{at}sri.utoronto.ca.

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