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代替Wntアゴニストは,カノニカルWntとβ-カテニンのシグナリングをフェノコピーする
Claudia Y Janda1, Luke T Dang2, Changjiang You3
1Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature
|May 4, 2017
まとめ
研究者は水溶性Wntアゴニストを開発し,特定のWnt信号伝達経路を活性化しました. これらの新しいアゴニストは伝統的なWntタンパク質の課題を克服し,再生医療におけるより良い研究と治療的応用を可能にします.
科学分野:
- 生物化学
- 細胞生物学
- 再生医療
背景:
- Wntタンパク質は,β-カテニンの信号伝達により,細胞増殖,分化,および幹細胞の自己再生を調節する.
- タンパク質の水性と交叉反応性は,機能的研究と治療的使用を複雑にする.
- Wntタンパク質のパルミトイロ化は分泌と受容体の相互作用に不可欠であるが,浄化を阻害する.
研究 の 目的:
- 本来のWntタンパク質の限界を克服する水溶性Wntアゴニストを開発する.
- 特定のFrizzled (FZD) 受容体相互作用を使用してWnt信号活性化を調査する.
- 再生医療におけるWntアゴニストの治療の可能性を探求する.
主な方法:
- 水溶性Frizzled-LRP5/LRP6の異体化剤を代替Wntアゴニストとして開発する.
- FZD5/FZD8特異的および広範なFZD反応性結合領域を使用しています.
- ベータカテニンのシグナリング応答,骨性系統のコミットメント,およびオルガノイド培養の成長の評価.
主要な成果:
- 代理Wntアゴニストは,WNT3Aに類似したFZD選択ベータカテニンシグナルを誘発した.
- メゼンキマ幹細胞の骨質分化が強化され,オルガノイドの成長が促進された.
- マウスの肝臓でWntの活性が実証され,代謝区画に影響を与え,肝細胞の増殖を促進する.
結論:
- 受容体ヘテロディメリゼーションを誘導するバイスペシフィックリガンドは,正規のWntシグナリングを活性化することができる.
- 簡単に生成される脂質のないWnt代用体は,機能的研究を容易にする.
- Wntサロゲートアゴニストは 再生医療の応用において有望な可能性を秘めています
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