Published Online
on October 6, 2005

A more recent version of this article appeared on November 1, 2005

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Submitted on June 26, 2004
Revised on December 8, 2004
Accepted on January 11, 2005

Nedd9 Protein, a Cas-L Homologue, Is Upregulated After Transient Global Ischemia in Rats. Possible Involvement of Nedd9 in the Differentiation of Neurons After Ischemia

Takahiro Sasaki MD, PhD; Satoshi Iwata MD, PhD; Hirotaka James Okano MD, PhD; Yasuyo Urasaki MS; Junichi Hamada MD, PhD; Hirotoshi Tanaka MD, PhD; Nam H. Dang MD, PhD; Hideyuki Okano MD, PhD; and Chikao Morimoto MD, PhD^*

From the Division of Clinical Immunology (T.S., S.I., Y.U., H.T., C.M.), Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; the Departments of Physiology (H.J.O., H.O.) and Neurology (T.S., J.H.), Keio University School of Medicine; Core Research for Evolutional Science and Technology (H.J.O., H.O.), Japan Science and Technology Agency, Saitama, Japan; and the Department of Lymphoma/Myeloma (N.H.D.), MD Anderson Cancer Center, University of Texas, TX.

^* To whom correspondence should be addressed. E-mail: morimoto{at}ims.u-tokyo.ac.jp.

Background and Purpose--Some proteins involved in self-repair after stroke in the adult brain are primarily expressed during embryonic development and strongly down-regulated during the early postnatal phase. Neuronal precursor cell-expressed, developmentally down-regulated gene (Nedd) 9 was recognized to be identical to Crk-associated substrate lymphocyte type (Cas-L), a docking protein that associates with a variety of signaling molecules, such as focal adhesion kinase (FAK), proline-rich tyrosine kinase 2 (Pyk2), and Crk. We investigated the involvement of these proteins in the pathophysiology of global cerebral ischemia.

Methods--The mouse Cas-L/Nedd9 cDNAs were cloned. The expression and function of Cas-L/Nedd9 protein in the pathogenesis of global ischemia in rats was investigated by RT-PCR, Western blot analysis, and immunohistochemistry. The neurite outgrowth of the transfectants of Nedd9 deletion mutants in PC-12 cells was also assessed to clarify the function of the Nedd9 protein.

Results--Nedd9 was a splicing variant of Cas-L and was selectively induced in neurons of the cerebral cortex and hippocampus 1 to 14 days after the ischemia. Induced Nedd9 protein was tyrosine phosphorylated and was bound to FAK in dendrite and soma of neurons after the ischemia. Finally, it was demonstrated that Nedd9 promoted neurite outgrowth of PC-12 cells.

Conclusions--Our study may support the potential of Nedd9 for participation in the differentiation of neurons after global ischemia in rats.

Key words: cerebral ischemia • global • rats • neural differentiation

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