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J. Biol. Chem., Vol. 283, Issue 9, 5287-5295, February 29, 2008

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Basic Fibroblast Growth Factor-induced Neuronal Differentiation of Mouse Bone Marrow Stromal Cells Requires FGFR-1, MAPK/ERK, and Transcription Factor AP-1^*

From the Research Laboratories, National Neuroscience Institute, Singapore 308433

It has been reported recently that bone marrow stromal cells (BMSCs) are able to differentiate into various neural cells both in vivo and in vitro (Egusa, H., Schweizer, F. E., Wang, C. C., Matsuka, Y., and Nishimura, I. (2005) J. Biol. Chem. 280, 23691–23697). However, the underlying mechanisms remain largely unknown. In this report, we have demonstrated that basic fibroblast growth factor (bFGF) alone effectively induces mouse BMSC neuronal differentiation. These differentiated neuronal cells exhibit characteristic electrophysiological properties and elevated levels of the neuronal differentiation marker, growth-associated protein-43 (GAP-43). To explore possible signaling pathways, we first analyzed the expression of various FGF receptors in mouse BMSCs. FGF receptor-1, -2, and -3 were detected, but only FGFR-1 was shown to be activated by bFGF. Small interfering RNA knock down of FGFR-1 in BMSCs significantly inhibited neuronal differentiation. Moreover, we have shown that the mitogen-activated protein kinase (ERK1/2) is persistently activated and blockage of ERK activity with the ERK-specific inhibitor U0126 prevents neuronal differentiation. It appears that activation of ERK cascade and neuronal differentiation of BMSCs induced by bFGF are independent of Ras activity but require functions of phospholipase C- pathway. Lastly, we examined the role of the immediate-early transcription factors AP-1 and NF-B and have found that phospholipase C--dependent c-Jun and ERK-dependent c-fos, but not the NF-B, are strongly activated by bFGF, which in turn regulates the neuronal differentiation of BMSCs.

Received for publication, August 20, 2007 , and in revised form, December 4, 2007.

^* This work was supported by National Medical Research Council of Singapore Grant NMRC 0735/2003 and Biomedical Research Council of Singapore Grant BMRC 05/1/33/19/410. 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: NNI Research, 11 Jalan Tan Tock Seng, Singapore. Tel.: 65-6357-7528; Fax: 65-62569178; E-mail: Zhi_Wei_Feng{at}nni.com.sg.

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