The epithelial glucocorticoid receptor is required for the normal timing of cell proliferation during mammary lobuloalveolar development but is dispensable for milk production.
Glucocorticoids have been shown to influence mammary gland function in vivo and to stimulate milk protein gene expression in vitro. Here, we describe the generation and analysis of a mouse model to study glucocorticoid receptor (GR, NR3C1) function in mammary epithelial cells. Using the Cre-loxP system, mutant mice were obtained in which the GR gene is specifically deleted in epithelial cells during lobuloalveolar development, leading to a complete loss of epithelial GR at the onset of lactation. Mice harboring the mammary-epithelial-specific GR mutation are able to nurse their litters until weaning. During pregnancy, however, GR deficiency delays lobuloalveolar development, leading to an incomplete epithelial penetration of the mammary fat pad that persists throughout lactation. We identified a reduced cell proliferation during lobuloalveolar development as reason for this delay. This reduction is compensated for by increased epithelial proliferation after parturition in the mutant glands. During lactation, GR-deficient mammary epithelium is capable of milk production and secretion. The expression of two milk proteins, namely whey acidic protein and beta-casein, during lactation was not critically affected in the absence of GR. We conclude that GR function is not essential for alveolar differentiation and milk production, but influences cell proliferation during lobuloalveolar development.
Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Tim M
TM
Wintermantel
Dagmar
D
Bock
Verena
V
Fleig
Erich F
EF
Greiner
Günther
G
Schütz
D000483:Alleles; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002364:Caseins / Q000378:metabolism; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008892:Milk / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D009154:Mutation; D017354:Point Mutation; D012313:RNA / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D015398:Signal Transduction
D002364:Caseins; D008894:Milk Proteins; D011965:Receptors, Glucocorticoid; C024471:whey acidic proteins; D012313:RNA; D001973:Bromodeoxyuridine