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The miR-424(322)/503 cluster orchestrates remodeling of the epithelium in the involuting mammary gland

机译:miR-424(322)/ 503簇可协调渐渐渐进的乳腺上皮的重塑

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摘要

The mammary gland is a very dynamic organ that undergoes continuous remodeling. The critical regulators of this process are not fully understood. Here we identify the microRNA cluster miR-424(322)/503 as an important regulator of epithelial involution after pregnancy. Through the generation of a knockout mouse model, we found that regression of the secretory acini of the mammary gland was compromised in the absence of miR-424(322)/503. Mechanistically, we show that miR-424(322)/503 orchestrates cell life and death decisions by targeting BCL-2 and IGF1R (insulin growth factor-1 receptor). Furthermore, we demonstrate that the expression of this microRNA cluster is regulated by TGF-β, a well-characterized regulator of mammary involution. Overall, our data suggest a model in which activation of the TGF-β pathway after weaning induces the transcription of miR-424(322)/503, which in turn down-regulates the expression of key genes. Here, we unveil a previously unknown, multilayered regulation of epithelial tissue remodeling coordinated by the microRNA cluster miR-424(322)/503.
机译:乳腺是一个非常动态的器官,会不断地重塑。这个过程的关键监管者尚未完全了解。在这里,我们确定microRNA簇miR-424(322)/ 503是妊娠后上皮退化的重要调控因子。通过生成基因敲除小鼠模型,我们发现在没有miR-424(322)/ 503的情况下,乳腺分泌性腺泡的退化受到损害。从机理上讲,我们显示miR-424(322)/ 503通过靶向BCL-2和IGF1R(胰岛素生长因子1受体)来协调细胞的生命和死亡决定。此外,我们证明了该microRNA簇的表达受TGF-β(一种特征明确的乳腺退化调控因子)调控。总体而言,我们的数据提示了一个模型,其中断奶后TGF-β途径的激活诱导miR-424(322)/ 503的转录,进而下调关键基因的表达。在这里,我们揭示了以前未知的,由microRNA簇miR-424(322)/ 503协调的上皮组织重塑的多层调节。

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