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


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Llobet-Navas D., Rodriguez-Barrueco R., Castro V., UGALDE A. P. , Sumazin P., Jacob-Sendler D., ...More

GENES & DEVELOPMENT, vol.28, no.7, pp.765-782, 2014 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 28 Issue: 7
  • Publication Date: 2014
  • Doi Number: 10.1101/gad.237404.114
  • Journal Name: GENES & DEVELOPMENT
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.765-782

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-beta, a well-characterized regulator of mammary involution. Overall, our data suggest a model in which activation of the TGF-b 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.