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First published online 18 March 2008
doi: 10.1242/jcs.025064
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Research Article |
1 Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
2 Bridgestone Laboratory of Developmental and Regenerative Neurobiology, Keio University School of Medicine, Tokyo 160-8582, Japan
3 Solution Oriented Research for Evolutional Science and Technology (SORST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
4 Laboratory for Cell Function and Dynamics, Advanced Technology Development Center, Brain Science Institute, RIKEN, Saitama 351-0198, Japan
5 Laboratory for Nanosystems Physiology, Research Institute for Electronic Science, Hokkaido University, Hokkaido 060-0812, Japan
6 Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
7 Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan
* Author for correspondence (e-mail: hidokano{at}sc.itc.keio.ac.jp)
Accepted 24 January 2008
During brain development, neural progenitor cells extend across the thickening brain wall and undergo mitosis. To understand how these two completely different cellular events are coordinated, we focused on the transcription pattern of the nestin gene (Nes), which encodes an intermediate filament protein strongly expressed in neural progenitor cells. To visualize nestin expression in vivo, we generated transgenic mice that expressed a destabilized fluorescent protein under the control of Nes second intronic enhancer (E/nestin:dVenus). During the neurogenic stage, when the brain wall thickens markedly, we found that nestin was regulated in a cell-cycle-dependent manner. Time-lapse imaging showed that nestin gene expression was upregulated during G1-S phase, when the neural progenitor cells elongate their fibers. However, nestin expression dramatically declined in G2-M phase, when progenitor cells round up to undergo mitosis. The cell-cycle-dependent phosphorylation of an upstream regulator class III POU transcription factor (Pou3f2 or Brn2) reduced its binding activity to the nestin core enhancer element and was therefore responsible for the decreased Nes transcription in G2-M phase. Collectively, these findings demonstrate precisely orchestrated gene regulation that correlates with the 3D morphological changes in neural progenitor cells in vivo.
Key words: Intermediate filament, Phosphorylation, Radial glia, POU, SOX, Cell cycle
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