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Molecular and Cellular Biology, December 2008, p. 7427-7441, Vol. 28, No. 24
0270-7306/08/$08.00+0 doi:10.1128/MCB.01962-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Stabilized β-Catenin Functions through TCF/LEF Proteins and the Notch/RBP-J
Complex To Promote Proliferation and Suppress Differentiation of Neural Precursor Cells
Takeshi Shimizu,1,2
Tetsushi Kagawa,1*
Toshihiro Inoue,1,2
Aya Nonaka,4
Shinji Takada,3
Hiroyuki Aburatani,4 and
Tetsuya Taga1,2*
Division of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo, Kumamoto, Kumamoto 860-0811, Japan,1 The 21st Century COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan,2 Center for Integrative Bioscience, Higashiyama, Myodaiji, Okazaki, Aichi 444-8585, Japan,3 Research Center for Advanced Science and Technology, Tokyo University, Komaba, Tokyo 4-6-1, Japan4
Received 31 October 2007/ Returned for modification 10 December 2007/ Accepted 1 October 2008
The proliferation and differentiation of neural precursor cells are mutually exclusive during brain development. Despite its importance for precursor cell self renewal, the molecular linkage between these two events has remained unclear. Fibroblast growth factor 2 (FGF2) promotes neural precursor cell proliferation and concurrently inhibits their differentiation, suggesting a cross talk between proliferation and differentiation signaling pathways downstream of the FGF receptor. We demonstrate that FGF2 signaling through phosphatidylinositol 3 kinase activation inactivates glycogen synthase kinase 3β (GSK3β) and leads to the accumulation of β-catenin in a manner different from that in the Wnt canonical pathway. The nuclear accumulated β-catenin leads to cell proliferation by activating LEF/TCF transcription factors and concurrently inhibits neuronal differentiation by potentiating the Notch1-RBP-J
signaling pathway. β-Catenin and the Notch1 intracellular domain form a molecular complex with the promoter region of the antineurogenic hes1 gene, allowing its expression. This signaling interplay is especially essential for neural stem cell maintenance, since the misexpression of dominant-active GSK3β completely inhibits the self renewal of neurosphere-forming stem cells and prompts their neuronal differentiation. Thus, the GSK3β/β-catenin signaling axis regulated by FGF and Wnt signals plays a pivotal role in the maintenance of neural stem/precursor cells by linking the cell proliferation to the inhibition of differentiation.
* Corresponding author. Mailing address: Division of Cell Fate Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, Kumamoto 860-0811, Japan. Phone: 81-96-373-6612. Fax: 81-96-373-6614. E-mail for Tetsushi Kagawa: kagawa{at}kumamoto-u.ac.jp. E-mail for Tetsuya Taga: taga{at}kumamoto-u.ac.jp
Published ahead of print on 13 October 2008.
Molecular and Cellular Biology, December 2008, p. 7427-7441, Vol. 28, No. 24
0270-7306/08/$08.00+0 doi:10.1128/MCB.01962-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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