プラリポテンシーからの脱出は,bHLH転写因子Tfe3の細胞内再分配によってゲートされます
Joerg Betschinger1, Jennifer Nichols, Sabine Dietmann
1Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. jb579@cam.ac.uk
Cell
|April 16, 2013
まとめ
腫瘍抑制剤であるFolliculin (Flcn) とTsc2は,Tfe3.3を調節することにより,胚性幹細胞 (ESC) の結合を防ぐ. 強制的な核Tfe3は多能性を維持し,系統へのコミットメントのためのレオスタットを明らかにします.
科学分野:
- 幹細胞生物学 幹細胞生物学とは
- プラリポテンスの分子メカニズム
- 細胞運命を決定する
背景:
- マウスの胚性幹細胞 (ESC) の自己再生はよく理解されています.
- プラリポテンシーからの脱出を制御する分子機構は,まだ十分に定義されていない.
研究 の 目的:
- ESCにおける多能性からの脱出を規制する要因を特定する.
- ESCのコミットメントにおけるFolliculin (Flcn) とTsc2の役割を明らかにする.
主な方法:
- 大規模な小さな干渉RNA (siRNA) スクリーン.
- ラパミシン (mTOR) 経路の哺乳類の標的の分析.
- 転写因子Tfe3の局所化と活性に関する研究.
- ゲノム全体の位置と機能分析.
- エピブラスト発達のインビボ研究.
主要な成果:
- Flcn と Tsc2 のノックダウンは,ESC のコミットメントを妨げています.
- FlcnはFnip1/2と共に核Tfe3を制限し,分化を促進する.
- 強制的な核のTfe3は,SECが差別化に抵抗することを可能にします.
- Tfe3はEsrrbを直接調節し,多能性回路に統合する.
- Flcn-Fnip1/2は,体内の発達中のTfe3の局所化に影響を与えます.
結論:
- Flcn-Tsc2-mTOR経路とFlcn-Fnip1/2-Tfe3軸は,プラリポテンスの不安定化のための細胞内部のレオスタットとして作用する.
- Tfe3は,多能性と差別化を統合する重要な調節剤です.
- Tfe3のFlcn媒介による調節は,表皮質の発達進行に不可欠である.
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