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J. Biol. Chem., Vol. 278, Issue 40, 38731-38739, October 3, 2003

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Leukemia Inhibitory Factor Receptor Signaling Negatively Modulates Nerve Growth Factor-induced Neurite Outgrowth in PC12 Cells and Sympathetic Neurons^*

Yu Pong Ng , Wei He  and Nancy Y. Ip, Recipient of the Croucher Foundation Senior Research Fellowship. 

From the Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

Nerve growth factor (NGF) is required for the development of sympathetic neurons and subsets of sensory neurons. Our current knowledge on the molecular mechanisms underlying the biological functions of NGF is in part based on the studies with PC12 rat pheochromocytoma cells, which differentiate into sympathetic neuron-like cells upon NGF treatment. Here we report that the expression of leukemia inhibitory factor receptor (LIFR), one of the signaling molecules shared by several neuropoietic cytokines of the interleukin-6 family, is specifically up-regulated in PC12 cells following treatment with NGF. Attenuation of LIFR signaling through stable transfection of antisense- or dominant negative-LIFR constructs enhances NGF-induced neurite extension in PC12 cells. On the contrary, overexpression of LIFR retards the growth of neurites. More importantly, whereas NGF-induced Rac1 activity is enhanced in antisense-LIFR and dominant negative-LIFR expressing PC12 cells, it is reduced in LIFR expressing PC12 cells. Following combined treatment with NGF and ciliary neurotrophic factor, sympathetic neurons exhibit attenuated neurite growth and branching. On the other hand, in sympathetic neurons lacking LIFR, neurite growth and branching is enhanced when compared with wild type controls. Taken together, our findings demonstrate that LIFR expression can be specifically induced by NGF and, besides its known function in cell survival and phenotype development, activated LIFR signaling can exert negative regulatory effects on neurite extension and branching of sympathetic neurons.

Received for publication, May 2, 2003 , and in revised form, July 18, 2003.

^* This study was supported in part by the Research Grants Council of Hong Kong (HKUST 6127/99 M and 2/99C) and the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01). 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Tel.: 852-2358-7304; Fax: 852-2358-2765; E-mail: BOIP{at}UST.HK.

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