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

• Published in: The Journal of biological chemistry Vol. 283; no. 9; pp. 5287 - 5295
• Main Authors: Yang, Haijie, Xia, Yinyan, Lu, Song Qing, Soong, Tuck Wah, Feng, Zhi Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-02-2008; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Butadienes - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Enzyme Inhibitors - pharmacology; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; GAP-43 Protein - metabolism; Humans; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Neurons - cytology; Neurons - metabolism; NF-kappa B - metabolism; Nitriles - pharmacology; Oncogene Protein p21(ras) - antagonists & inhibitors; Oncogene Protein p21(ras) - metabolism; Phospholipase C gamma - antagonists & inhibitors; Phospholipase C gamma - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Receptor, Fibroblast Growth Factor, Type 1 - agonists; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Receptor, Fibroblast Growth Factor, Type 2 - agonists; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Receptor, Fibroblast Growth Factor, Type 3 - agonists; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Stromal Cells - cytology; Stromal Cells - metabolism; Transcription Factor AP-1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M706917200

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-γ pathway. Lastly, we examined the role of the immediate-early transcription factors AP-1 and NF-κB and have found that phospholipase C-γ-dependent c-Jun and ERK-dependent c-fos, but not the NF-κB, are strongly activated by bFGF, which in turn regulates the neuronal differentiation of BMSCs.