Conversion of the nipple to hair-bearing epithelia by lowering bone morphogenetic protein pathway activity at the dermal-epidermal interface.
Epithelial appendages, such as mammary glands and hair, arise as a result of epithelial-mesenchymal interactions. Bone morphogenetic proteins (BMPs) are important for hair follicle morphogenesis and cycling and are known to regulate a wide variety of developmental processes. For example, overexpression of BMPs inhibits hair follicle formation. We hypothesized that the down-regulation of the BMP signaling pathway in the basal epidermis expands regions that are competent to form hair follicles and could alter the fate of the epithelium in the mouse nipple to a hair-covered epidermal phenotype. To test our hypothesis, we used a transgenic mouse model in which keratin 14 (KRT14) promoter-mediated overexpression of Noggin, a BMP antagonist, modulates BMP activity. We observed the conversion of nipple epithelium into pilosebaceous units. During normal mammary gland organogenesis, BMPs are likely used by the nipple epithelium to suppress keratinocyte differentiation, thus preventing the formation of pilosebaceous units. In this report, we characterize the morphology and processes that influence the development of hairs within the nipple of the KRT14-Noggin mouse. We demonstrate that Noggin acts, in part, by reducing the BMP signal in the epithelium. Reduction of the BMP signal in turn leads to a reduction in the levels of parathyroid hormone-related protein. We propose that during evolution of the nipple, the BMP pathway was co-opted to suppress hair follicle formation and create a more functional milk delivery apparatus.
Mayer
Julie Ann
JA
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Foley
John
J
De La Cruz
Damon
D
Chuong
Cheng-Ming
CM
Widelitz
Randall
R
D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D020405:Dermis / Q000166:cytology* / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006197:Hair / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D018859:Hair Follicle / Q000166:cytology / Q000648:ultrastructure; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009558:Nipples / Q000166:cytology* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D051785:Smad Proteins; D000099176:Noggin Protein; C465570:Shh protein, mouse