期刊
MOLECULAR BRAIN
卷 2, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1756-6606-2-16
关键词
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资金
- National Institute of Health [NS047344, AG024984, MH084018]
- McKnight Foundation
- NARSAD
- Robert Packard Center for ALS Research at Johns Hopkins
- MDA
- Maryland Stem Cell Research Fund
- IMHRO
- NATIONAL INSTITUTE OF MENTAL HEALTH [P20MH084018] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS047344] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG024984] Funding Source: NIH RePORTER
Background: Neural stem cells (NSCs) are present in the adult mammalian brain and sustain lifelong 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.
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