Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development.
Prior reports have demonstrated that both parathyroid hormone-related protein (PTHrP) and the type I PTH/PTHrP receptor are necessary for the proper development of the embryonic mammary gland in mice. Using a combination of loss-of-function and gain-of-function models, we now report that PTHrP regulates a series of cell fate decisions that are central to the survival and morphogenesis of the mammary epithelium and the formation of the nipple. PTHrP is made in the epithelial cells of the mammary bud and, during embryonic mammary development, it interacts with the surrounding mesenchymal cells to induce the formation of the dense mammary mesenchyme. In response, these mammary-specific mesenchymal cells support the maintenance of mammary epithelial cell fate, trigger epithelial morphogenesis and induce the overlying epidermis to form the nipple. In the absence of PTHrP signaling, the mammary epithelial cells revert to an epidermal fate, no mammary ducts are formed and the nipple does not form. In the presence of diffuse epidermal PTHrP signaling, the ventral dermis is transformed into mammary mesenchyme and the entire ventral epidermis becomes nipple skin. These alterations in cell fate require that PTHrP be expressed during development and they require the presence of the PTH/PTHrP receptor. Finally, PTHrP signaling regulates the epidermal and mesenchymal expression of LEF1 and (&bgr;)-catenin, suggesting that these changes in cell fate involve an interaction between the PTHrP and Wnt signaling pathways.
Foley
J
J
Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
Dann
P
P
Hong
J
J
Cosgrove
J
J
Dreyer
B
B
Rimm
D
D
Dunbar
M
M
Philbrick
W
W
Wysolmerski
J
J
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D003598:Cytoskeletal Proteins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology*; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006651:Histocytochemistry; D051821:Lymphoid Enhancer-Binding Factor 1; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009558:Nipples / Q000166:cytology / Q000196:embryology*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000032:analysis; D019076:Transgenes / Q000235:genetics; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin