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J. Biol. Chem., Vol. 279, Issue 31, 32643-32650, July 30, 2004
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¶
From the
Department of Neurobiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan and the
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Ephrins are cell surface-associated ligands for Eph receptor tyrosine kinases and are implicated in repulsive axon guidance and cell migration. EphA2, 3, and 4 receptors and one of their cognate ligands, ephrin-A2, are expressed by cells in the subventricular zone and ganglionic eminence of the embryonic day 14.5 telencephalon and by neural precursor cells in vitro. Activation of EphA receptors in dissociated neural precursor cells in vitro facilitates the commitment to neuronal fates. The majority of ephrin-A1-induced neurons is immunoreactive for tyrosine hydroxylase. Blocking the signal by the extracellular domain of EphA in forebrain slices results in a decrease in neurogenesis. Extracellular signal-regulated kinase is activated by the ligand binding to EphA receptors and is involved in the neurogenesis through EphA receptors. Rap1, but not Ras, is activated in response to ephrin-A1. Our results identify EphA receptors as positive regulators of the mitogen-activated protein kinase pathway that exerts neurogenesis of neural precursor cells from the developing central nervous system.
Received for publication, December 4, 2003 , and in revised form, May 11, 2004.
* This work was partly supported by the 21st Century Center of Excellence Program, 32 Grant-in-aid 14657343 from the Ministry of Education, Culture, Sports and Technology of Japan, and Research Grant 15A-2 for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare. 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.
¶ To whom correspondence should be addressed: Dept. of Neurobiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: 81-43-2262024; Fax: 81-43-2262025; E-mail: t-yamashita{at}faculty.chiba-u.jp.
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