Functional rescue of Stat5a-null mammary tissue through the activation of compensating signals including Stat5b.
Prolactin induces mammopoiesis and lactogenesis through the Janus kinase-signal transducers and activators of transcription pathway, with Stat5a being a principal and obligate cytoplasmic and nuclear signaling molecule. Mice from which the Stat5a gene has been deleted fail to develop functional mammary tissue during their first pregnancy. Lobuloalveolar outgrowth is curtailed, and epithelial cells fail to progress to functional differentiation. Here, we investigate whether the effect of Stat5a deficiency is restricted to the epithelium and whether the gland has the capacity to activate alternative signaling pathways that could restore development and function. Mammary gland transplant experiments showed that Stat5a-deficient epithelium does not differentiate in wild-type stroma, thus demonstrating a cell-autonomous role for Stat5a. The capacity of Stat5a-deficient mammary tissue to develop and secrete milk was measured after consecutive pregnancies and with postpartum suckling. Neither of these regimens could independently restore lactation. However, the combination of several pregnancies and suckling stimuli resulted in a partial establishment of lactation and an increase of Stat5b activity. These experiments demonstrate that the mammary gland has inherent plasticity that allows it to use different signals to achieve its ultimate purpose, the production of milk to nurture newborn offspring.
Liu
X
X
Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
Gallego
M I
MI
Smith
G H
GH
Robinson
G W
GW
Hennighausen
L
L
D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D004848:Epithelium / Q000254:growth & development; D005260:Female; D006801:Humans; D007774:Lactation / Q000235:genetics / Q000502:physiology; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008894:Milk Proteins; D011247:Pregnancy; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins