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J. Biol. Chem., Vol. 279, Issue 41, 43245-43253, October 8, 2004

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Neuronal Roles of the Integrin-associated Protein (IAP/CD47) in Developing Cortical Neurons^*

Tadahiro Numakawa, Tetsuya Ishimoto¶, Shingo Suzuki||, Yumiko Numakawa**, Naoki Adachi||, Tomoya Matsumoto¶, Daisaku Yokomaku¶, Hisatsugu Koshimizu||, Kazuhiro E. Fujimori¶, Ryota Hashimoto, Takahisa Taguchi¶, and Hiroshi Kunugi

From the Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry of Japan, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan, the ^¶Neuronics R.G. Special Division for Human Life Technology and the ^**Human Stress Signal Research Center, National Institute of Advanced Industrial ^**Science and Technology (AIST), Midorigaoka, Ikeda, Osaka 563-8577, Japan, and the ^||Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan

Little is known about the role of the integrin-associated protein (IAP, or CD47) in neuronal development and its function in the central nervous system. We investigated neuronal responses in IAP-overexpressing cortical neurons using a virus-gene transfer system. We found that dendritic outgrowth was significantly enhanced in IAP (form 4)-transfected neurons. Furthermore, synaptic proteins including synaptotagmin, syntaxin, synapsin I, and SNAP25 (25-kDa synaptosomal associated protein) were up-regulated. In accordance with this finding, the release of the excitatory transmitter glutamate and the frequencies of Ca²⁺ oscillations (glutamate-mediated synaptic transmission) were increased. Interestingly, the overexpression of IAP activated mitogen-activated protein kinase (MAPK), and this activation was required for the IAP-dependent biological effects. After down-regulation of the endogenous IAP by small interfering RNA, MAPK activity, synaptic protein levels, and glutamate release decreased. These observations suggest that the IAP plays important roles in dendritic outgrowth and synaptic transmission in developing cortical neurons through the activation of MAPK.

Received for publication, June 16, 2004 , and in revised form, August 2, 2004.

^* 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 supplementary Figs. 1-4, which present further data on IAP-mediated effects on cortical cultures.

To whom correspondence should be addressed. Tel.: 81-42-341-2711 (ext. 5132); Fax: 81-42-346-1744; E-mail: numakawa{at}ncnp.go.jp.

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