HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland.
During pregnancy the mammary epithelium and its supporting vasculature rapidly expand to prepare for lactation, resulting in dramatic changes in the micro-environment. In order to investigate the role of oxygenation and metabolism in these processes, the oxygen-responsive component of the hypoxia-inducible factor (HIF) 1 complex, HIF1alpha, was deleted in the murine mammary gland. Although vascular density was unchanged in the HIF1alpha null mammary gland, loss of HIF alpha impaired mammary differentiation and lipid secretion, culminating in lactation failure and striking changes in milk composition. Transplantation experiments confirmed that these developmental defects were mammary epithelial cell autonomous. These data make clear that HIF1alpha plays a critical role in the differentiation and function of the mammary epithelium.
Seagroves
Tiffany N
TN
Division of Biological Sciences, Molecular Biology Section, University of California San Diego, La Jolla, CA 92093, USA.
Hadsell
Darryl
D
McManaman
Jim
J
Palmer
Carol
C
Liao
Debbie
D
McNulty
Wayne
W
Welm
Bryan
B
Wagner
Kay-Uwe
KU
Neville
Margaret
M
Johnson
Randall S
RS
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007774:Lactation / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008892:Milk / Q000737:chemistry; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism; D011247:Pregnancy; D011897:Random Allocation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D010100:Oxygen