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microRNA-875-5pは歯の発生において上皮―間葉相互作用における間葉細胞の凝集に重要な役割を果たす

鮒田, 啓太 FUNADA, Keita フナダ, ケイタ 九州大学

2020.09.25

概要

上皮−間葉相互作用は、肺、腎臓、毛、唾液腺および歯といった様々な器官の発生に重要であり、これらの器官は、上皮の肥厚および間葉細胞の凝集という共通のイベントを経て、様々なシグナル経路により発生制御が行われている。歯においては、神経堤細胞から分化した歯原性間葉細胞の凝集に PDGF シグナルが関与することが知られているがその詳細は不明である。今回我々は、歯における上皮−間葉相互作用の分子メカニズムを解明するため、 cap analysis of gene expression (CAGE) 解析を用いて歯に特異的に発現している転写開始点を網羅的に検索した。その結果、クロモソーム 15qD1 領域に、歯に特異的な転写開始点を発見し、同部位から microRNA-875 (miR875)が転写されている可能性を見出した。そこで、胎生 11 日齢 (E11)から生後 7 日齢マウス歯胚より total RNA を抽出し、発現解析を行ったところ miR875-5p は発生初期の歯胚間葉細胞に発現していることが判明した。さらに、Luciferase assay にて歯胚の形態形成に関与している Prrx1/2 が mir875 のプロモーター領域に結合し転写を促進している可能性を示した。次に、miR875-5p の歯胚間葉細胞における機能を解析するため、マウス歯原性間葉細胞株（mouse dental pulp cell : mDP cell）に mimic miR875-5p を遺伝子導入したところ、歯胚上皮細胞への遊走がみられ、PDGF 添加により相乗的に遊走能が亢進することを発見した。さらに、miR875 がPDGF シグナルに抑制的に作用する PTEN、および細胞遊走に影響を与えていることが知られる Stat1の発現を抑制していることを解明した。これらの結果から、miR875 は歯の発生初期に特異的に発現し、PDGF シグナル経路を活性化し、間葉細胞の凝集を誘導することで、上皮−間葉相互作用を制御している可能性が示唆された。

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