小肠隐窝底部的潘氏细胞分泌抗菌肽、酶和生长因子，有助于清除病原体和维持干细胞生态位。潘氏细胞的丢失及其功能障碍通常发生在各种病理中，但控制潘氏细胞功能的机制仍然很大程度上未知。在这里，我们通过与 RNA 结合蛋白 HuR 相互作用改变 SOX9 翻译，将 microRNA-195 (miR-195) 确定为潘氏细胞发育和活性的抑制因子。肠上皮中 miR-195 (miR195-Tg) 的组织特异性转基因表达降低了小鼠粘膜 SOX9 的水平并减少了溶菌酶阳性 (Paneth) 细胞的数量。在源自 miR-195-Tg 小鼠的肠道类器官中异位表达的 SOX9 可恢复潘氏细胞离体发育。 miR-195不与Sox9 mRNA结合，但它直接与HuR相互作用并阻止HuR与Sox9 mRNA结合，从而抑制SOX9翻译。与 miR-195-Tg 小鼠相比，携带 Sox9 转基因和 HuR 基因座消融的小鼠的肠粘膜显示出较低水平的 SOX9 蛋白和潘氏细胞数量。 miR-195 的特异性 antagomir 抑制其活性可改善 HuR 缺陷的肠道类器官中的潘氏细胞功能。这些结果表明 miR-195 与 HuR 的相互作用通过改变小肠上皮中 SOX9 的翻译来调节潘氏细胞功能。

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.