C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland.
The CCAAT/enhancer binding proteins (C/EBPs) are differentially expressed throughout mammary gland development and interact with binding sites within the promoter of a milk protein gene, beta-casein. The specific roles of C/EBPbeta and C/EBPalpha in mouse mammary gland development and differentiation have been investigated in mice that carry targeted deletions of these genes. C/EBPbeta-/- virgin mice exhibited cystic, enlarged mammary ducts with decreased secondary branching. Transplantation of C/EBPbeta-/- mammary epithelium into the cleared mammary fat pads of nude mice confirmed that this defect in ductal morphogenesis was intrinsic to the epithelium. When treated with estrogen/progesterone (E+P) to simulate pregnancy, C/EBPbeta-/- mammary glands displayed only limited lobuloalveolar development and ductal side branching. Primary mammary epithelial cells obtained from E+P-treated C/EBPbeta-/- mice that were cultured on extracellular matrix gels did not functionally differentiate in response to lactogenic hormones despite their organization into three-dimensional structures. Expression of beta-casein protein was inhibited 85%-100% and whey acidic protein (WAP) was undetectable. In contrast, no detectable alterations in mammary development or beta-casein expression were observed in mammary outgrowths derived from newborn C/EBPalpha-/- mammary epithelium transplanted into the cleared mammary fat pads of syngeneic hosts. These results demonstrate that C/EBPbeta, but not C/EBPalpha, is required for ductal morphogenesis, lobuloalveolar development, and functional differentiation of mammary epithelial cells.
Seagroves
T N
TN
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Krnacik
S
S
Raught
B
B
Gay
J
J
Burgess-Beusse
B
B
Darlington
G J
GJ
Rosen
J M
JM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins; D002364:Caseins / Q000037:antagonists & inhibitors / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008894:Milk Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009024:Morphogenesis / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D016378:Tissue Transplantation; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D022762:CCAAT-Enhancer-Binding Proteins; D002364:Caseins; D004268:DNA-Binding Proteins; D004967:Estrogens; D008894:Milk Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C024471:whey acidic proteins; D011374:Progesterone