Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells

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 ce...

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Bibliographic Details
Published in:Molecular and cellular biology 2008-12, Vol.28 (24), p.7427-7441
Main Authors: Shimizu, Takeshi, Kagawa, Tetsushi, Inoue, Toshihiro, Nonaka, Aya, Takada, Shinji, Aburatani, Hiroyuki, Taga, Tetsuya
Format: Article
Language:English
Subjects:
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
beta Catenin - genetics
beta Catenin - metabolism
Cell Cycle - physiology
Cell Differentiation - physiology
Cell Proliferation
Cells, Cultured
Cyclin D1 - genetics
Cyclin D1 - metabolism
Enzyme Activation
Enzyme Inhibitors - metabolism
Glycogen Synthase Kinase 3 - genetics
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism
Mice
Neurons - cytology
Neurons - physiology
NIH 3T3 Cells
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Promoter Regions, Genetic
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
RNA Interference
Signal Transduction - physiology
Stem Cells - cytology
Stem Cells - physiology
TCF Transcription Factors - genetics
TCF Transcription Factors - metabolism
Transcription Factor HES-1
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Summary: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 3beta (GSK3beta) and leads to the accumulation of beta-catenin in a manner different from that in the Wnt canonical pathway. The nuclear accumulated beta-catenin leads to cell proliferation by activating LEF/TCF transcription factors and concurrently inhibits neuronal differentiation by potentiating the Notch1-RBP-Jkappa signaling pathway. beta-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 GSK3beta completely inhibits the self renewal of neurosphere-forming stem cells and prompts their neuronal differentiation. Thus, the GSK3beta/beta-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.
ISSN:1098-5549
DOI:10.1128/mcb.01962-07