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J. Biol. Chem., Vol. 282, Issue 44, 32462-32470, November 2, 2007

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The Sonic Hedgehog Pathway Mediates Carbamylated Erythropoietin-enhanced Proliferation and Differentiation of Adult Neural Progenitor Cells^*

Lei Wang, Zheng Gang Zhang¹, Sara R. Gregg, Rui Lan Zhang, Zhongxian Jiao, Yvonne LeTourneau, Xianshuang Liu, Yifan Feng, Jens Gerwien, Lars Torup^¶, Marcel Leist^||, Constance Tom Noguchi^**, Zhi-Yong Chen^**, and Michael Chopp

From the Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, Department of Physics, Oakland University, Rochester, Michigan 48309, Drug Metabolism and ^¶Neuropharmacology, H. Lundbeck A/S, 2500 Valby, Denmark, ^||Department of Biology, University of Konstanz, D-78457 Konstanz, Germany, and ^**Molecular Cell Biology Section, Laboratory of Chemical Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

Carbamylated erythropoietin (CEPO), a well characterized erythropoietin (EPO) derivative, does not bind to the classical EPO receptor and does not stimulate erythropoiesis. Using neural progenitor cells derived from the subventricular zone of the adult mouse, we investigated the effect of CEPO on neurogenesis and the associated signaling pathways in vitro. We found that CEPO significantly increased neural progenitor cell proliferation and promoted neural progenitor cell differentiation into neurons, which was associated with up-regulation of Sonic hedgehog (Shh), its receptor ptc, and mammalian achaete-scute homolog 1 (Mash1), a pro-neuron basic helix-loop-helix protein transcription factor. Blockage of the Shh signaling pathway with a pharmacological inhibitor, cyclopamine, abolished the CEPO-induced neurogenesis. Attenuation of endogenous Mash1 expression by short-interfering RNA blocked CEPO-promoted neuronal differentiation. In addition, recombinant mouse Shh up-regulated Mash1 expression in neural progenitor cells. These results demonstrate that the Shh signaling pathway mediates CEPO-enhanced neurogenesis and Mash1 is a downstream target of the Shh signaling pathway that regulates CEPO-enhanced neuronal differentiation.

Received for publication, August 17, 2007

^* This work was supported by NINDS, National Institutes of Health Grants PO1 NS23393, PO1 NS42345, RO1NS43324, and RO1HL 64766. 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.

¹ To whom correspondence should be addressed: Dept. of Neurology, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202. Tel.: 313-916-5456; Fax: 313-916-1318; E-mail: zhazh{at}neuro.hfh.edu.

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