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Genes Dev. 2014 Apr 1;28(7):765-82. doi: 10.1101/gad.237404.114. Epub 2014 Mar 17.

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

Author information

1
Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York 10032, USA;

Abstract

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.

KEYWORDS:

BCL2; IGF1R; TGFβ; mammary gland development; miR-424; miR-503

PMID:
24636986
PMCID:
PMC4015488
DOI:
10.1101/gad.237404.114
[Indexed for MEDLINE]
Free PMC Article
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