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Molecular genetic analysis of FGFR1 signalling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells

Dengke K Ma12, Karthikeyan Ponnusamy3, Mi-Ryoung Song25, Guo-li Ming124 and Hongjun Song124*

Author Affiliations

1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

2 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

3 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

4 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

5 Bioimaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea

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Molecular Brain 2009, 2:16  doi:10.1186/1756-6606-2-16

Published: 8 June 2009

Abstract

Background

Neural stem cells (NSCs) are present in the adult mammalian brain and sustain life-long adult neurogenesis in the dentate gyrus of the hippocampus. In culture, fibroblast growth factor-2 (FGF-2) is sufficient to maintain the self-renewal of adult NSCs derived from the adult rat hippocampus. The underlying signalling mechanism is not fully understood.

Results

In the established adult rat NSC culture, FGF-2 promotes self-renewal by increasing proliferation and inhibiting spontaneous differentiation of adult NSCs, accompanied with activation of MAPK and PLC pathways. Using a molecular genetic approach, we demonstrate that activation of FGF receptor 1 (FGFR1), largely through two key cytoplasmic amino acid residues that are linked to MAPK and PLC activation, suffices to promote adult NSC self-renewal. The canonical MAPK, Erk1/2 activation, is both required and sufficient for the NSC expansion and anti-differentiation effects of FGF-2. In contrast, PLC activation is integral to the maintenance of adult NSC characteristics, including the full capacity for neuronal and oligodendroglial differentiation.

Conclusion

These studies reveal two amino acid residues in FGFR1 with linked downstream intracellular signal transduction pathways that are essential for maintaining adult NSC self-renewal. The findings provide novel insights into the molecular mechanism regulating adult NSC self-renewal, and pose implications for using these cells in potential therapeutic applications.