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Dev Biol. 2014 Nov 15;395(2):245-54. doi: 10.1016/j.ydbio.2014.09.012. Epub 2014 Sep 16.

The STAT5-regulated miR-193b locus restrains mammary stem and progenitor cell activity and alveolar differentiation.

Author information

1
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Microbiology, Dankook University, Cheonan 330-714, Republic of Korea.
3
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lotharh@mail.nih.gov.

Abstract

The transcription factor STAT5 mediates prolactin signaling and controls functional development of mammary tissue during pregnancy. This study has identified the miR-193b locus, also encoding miRNAs 365-1 and 6365, as a STAT5 target in mammary epithelium. While the locus was characterized by active histone marks in mammary tissue, STAT5 binding and expression during pregnancy, it was silent in most non-mammary cells. Inactivation of the miR-193b locus in mice resulted in elevated mammary stem/progenitor cell activity as judged by limiting dilution transplantation experiments of primary mammary epithelial cells. Colonies formed by mutant cells were larger and contained more Ki-67 positive cells. Differentiation of mammary epithelium lacking the miR-193b locus was accelerated during puberty and pregnancy, which coincided with the loss of Cav3 and elevated levels of Elf5. Normal colony development was partially obtained upon ectopically expressing Cav3 or upon siRNA-mediated reduction of Elf5 in miR-193b-null primary mammary epithelial cells. This study reveals a previously unknown link between the mammary-defining transcription factor STAT5 and a microRNA cluster in controlling mammary epithelial differentiation and the activity of mammary stem and progenitor cells.

KEYWORDS:

Alveoli, Differentiation; Development; Mammary; Micro RNAs; STAT5; Stem cells; miR-193b

PMID:
25236432
PMCID:
PMC4252501
DOI:
10.1016/j.ydbio.2014.09.012
[Indexed for MEDLINE]
Free PMC Article

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