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Tracing the evolutionary history of blood cells to the unicellular ancestor of animals

Nagahata, Yosuke 京都大学 DOI:10.14989/doctor.r13526

2023.01.23

概要

ヒトの血液には、赤血球や血小板(栓球)、リンパ球、貪食細胞などの様々な系列の細胞が存在している。これらの多くは脊椎動物に固有の系列であるが、貪食細胞は、無脊椎動物を含むほとんど全ての動物に共通して存在している。この事実を基に、動物の進化において、様々な系列の血液細胞は貪食細胞を起源として出現したと考えられてきた。しかし、これは、現存している種の形質からの推測であり、遺伝学的証拠が乏しく、異なる起源を持つ細胞が類似の貪食細胞へと収斂進化を遂げた可能性も十分に考えられる。そこで、本研究では、様々な生物種・細胞系列の遺伝子発現状態を比較することで、血液細胞の起源が同一であるのか、又、同一であった場合にその起源はどこまで遡れるのかを検証し、血液細胞の進化の足跡を辿ることとした。

研究対象の生物種として、マウス、ホヤ、カイメン、カプサスポラを調査した。カプサスポラは、アメーバ形態と凝集形態と遷移する、動物に近縁な真核単細胞生物である。まず、これら4 生物種の遺伝子を比較したところ、3237 個の相同遺伝子群が同定された。これらの相同遺伝子に基づいて遺伝子発現状態を比較したところ、マウス、ホヤ、カイメンの貪食細胞は互いに類似しており、さらにカプサスポラとの類似性も示された。これにより、貪食細胞が血液細胞の原型であるとともに、その起源が同一で、単細胞生物にまで遡られることが示された。貪食細胞とカプサスポラとの類似性を規定している遺伝子を探るため、両者に高発現している遺伝子を調べると、転写因子では唯一CEBPが同定された。 4 生物種の CEBPを、マウスの B 細胞や巨核球などの前駆細胞に強制発現させると、これらの前駆細胞が貪食細胞へと系列転換した。即ち、貪食細胞を規定するという CEBPの機能が単細胞生物からマウスまで保存されてきたことが示された。

次に、マウスの血液細胞における系列の多様性の維持機構を探索した。T 細胞やB 細胞などの非貪食系血液前駆細胞に CEBPを強制発現させると、貪食細胞へと系列転換してしまうことから、これらの前駆細胞では CEBPは何らかの機構により抑制される必要がある。このCEBP抑制機構の候補として、ポリコム複合体に注目した。ChIP などの実験により、ポリコム複合体の構成要素であるRing1A/B によってCEBPが抑制されていることが確認された。Ring1A/B をin vivo で欠失させると、T 細胞、B 細胞、赤血球、巨核球の前駆細胞が減少し、また、in vitro で欠失させると、これらの前駆細胞が貪食細胞へと系列転換することも見出した。Ring1A/B の欠失により生じた貪食細胞は、正常の貪食細胞と比較して、遺伝子発現状態がカプサスポラにより近いことも発見した。

以上より、動物の共通祖先において、体腔中の細胞が CEBPを発現し、単細胞生物時代の形質を継承して貪食細胞となり、これが血液細胞の起源となったと推察される。その後、脊椎動物は、ポリコムによる CEBP抑制という共通の機構により、多様な系列を獲得したと考えられる。また、カプサスポラの凝集形態はアメーバ形態に比して、CEBP発現量が低くRing1A/B 発現量が高いことも見出し、ポリコムによるCEBP抑制が、単細胞生物から多細胞生物への進化においても重要であった可能性も示唆された。

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