Mammary epithelial cells are not able to undergo pregnancy-dependent differentiation in the absence of the helix-loop-helix inhibitor Id2.
Mammary alveolar development during pregnancy is triggered by hormone signals. The prolactin receptor/Jak2/signal transducer and activator of transcription (Stat) 5 signal transduction pathway is the principal mediator of these cues and alveolar development is abrogated in its absence. The loss of the basic helix-loop-helix protein inhibitor of differentiation (Id)2 results in a similar defect. To investigate the role of Id2 in mammary epithelium, we performed structural and molecular analyses. Id2-null mammary epithelial cells were unable to form alveoli; the epithelial architecture was disorganized and dissimilar from early stages of alveologenesis in wild-type glands. The epithelial cells retained the ductal marker Na-K-Cl cotransporter (NKCC)1. Nuclear localization of Stat5a and down-regulation of NKCC1 was observed in some areas, indicating a limited response to pregnancy signals. The differentiation status of Id2-null tissue at term was further characterized with cDNA microarrays enriched in mammary specific sequences (mammochip). Some of the early differentiation markers for mammary epithelium were expressed in the Id2-null tissue, whereas genes that are expressed at later stages of pregnancy were not induced. From these results, we conclude that, in the absence of Id2, mammary epithelial development is arrested at an early stage of pregnancy.
Miyoshi
Keiko
K
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Building 8, Room 101, 8 Center Drive, Bethesda, MD 20892, USA.
Meyer
Barbara
B
Gruss
Peter
P
Cui
Yongzhi
Y
Renou
Jean-Pierre
JP
Morgan
Fanta V
FV
Smith
Gilbert H
GH
Reichenstein
Moshe
M
Shani
Moshe
M
Hennighausen
Lothar
L
Robinson
Gertraud W
GW
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000032:analysis / Q000172:deficiency* / Q000502:physiology; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D005260:Female; D018257:Helix-Loop-Helix Motifs; D051797:Inhibitor of Differentiation Protein 2; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008894:Milk Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D028021:Sodium-Potassium-Chloride Symporters / Q000032:analysis / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D015534:Trans-Activators / Q000032:analysis; D014157:Transcription Factors / Q000172:deficiency* / Q000502:physiology
D015415:Biomarkers; D004268:DNA-Binding Proteins; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D008894:Milk Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors