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.2008 Nov;173(5):1339-48.
doi: 10.2353/ajpath.2008.070920. Epub 2008 Oct 2.

Conversion of the nipple to hair-bearing epithelia by lowering bone morphogenetic protein pathway activity at the dermal-epidermal interface

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Conversion of the nipple to hair-bearing epithelia by lowering bone morphogenetic protein pathway activity at the dermal-epidermal interface

Julie Ann Mayer et al. Am J Pathol.2008 Nov.

Abstract

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.

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Figures

Figure 1
Figure 1
Expression of Noggin and BMP signaling in nipples of 6- to 8-month-old WT, Noggin-overexpressing, andMsx2−/− mice.a: Nipples were harvested from WT and transgenic mice and analyzed for levels of endogenous Noggin, ectopic levels of KRT14-Noggin, Bmpr1a, and control L32 genes by RT-PCR.b: ANoggin-lacZ mouse was used to locate Noggin expression and further confirmed byin situ hybridization for Noggin on a control nipple.
Figure 2
Figure 2
Scanning electron microscopy and quantitation of hair follicles from adult, 6 to 8 months old, parous mice.a andc: Control andMsx2−/− mice show no hair follicles within the nipple.b andd: Noggin-overexpressing mice show ectopic hair follicles extruding from the nipples.e: A graph indicates the trend that increased hair follicle numbers correlates with increasing Noggin expression.Arrows point to an example of a hair follicle growing within the nipple. Scale bar = 200 μm.
Figure 3
Figure 3
Histological and immunohistochemical analysis of adult, parous 6- to 8-month-old WT and transgenic mouse nipples with decreased BMP activity. H&E-stained sections of control (a),KRT14-Noggin+/− (b),KRT14-Noggin+/+ (c), andMsx2−/− mice (d).e–h: Oil Red O staining to indicate the presence of sebaceous glands in the Noggin-overexpressing mice compared toMsx2−/− and control mice. KRT14 immunostaining showing no change in nipple epithelium from control, Noggin-overexpressing transgenic, orMsx2−/− mice (i–l) but increased epithelial expression surrounding ectopic hair follicles in Noggin-overexpressing mice (j,k).Redarrows point to pilosebaceous units. Scale bar = 200 μm.
Figure 4
Figure 4
Immunohistochemical analysis of proliferation, differentiation, and apoptosis of adult, parous, 6- to 8-month-old WT and transgenic mouse nipples with decreased BMP activity. Control (a),KRT14-Noggin+/− (b),KRT14-Noggin+/+ (c), andMsx2−/− (d) mouse nipples stained for Ki-67 to detect proliferating cells.e–h: NCAM staining for mesenchymal cells.i–l: TUNEL staining to locate apoptotic cells. The percent Ki-67 (m)- and TUNEL (n)-positive epithelial (blue bars) and dermal (green bars) cells were quantified and the average and SD determined (n = 3). Scale bar = 200 μm.
Figure 5
Figure 5
Expression patterns for PTHrP, Shh, and pSmad1/5/8 in the nipples of adult, parous, 6- to 8-month-old WT, Noggin-overexpressing, andMsx2−/− mice.a–d: PTHrP expression appears to decrease in a dose-dependent manner in Noggin-overexpressing mice compared to WT andMsx2−/− mice.e–h: Noggin-overexpressing mice show an increase in epithelial Shh expression surrounding the ectopic hair follicles but no change in nipple epithelial expression compared to control andMsx2−/− mice.i–l: p-Smad1/5/8 immunostaining is reduced in the nipple epithelium and increased in the epithelium surrounding the ectopic hair follicles in Noggin-overexpressing mice compared to WT andMsx2−/− mice.Redarrows inb andc indicate areas with reduced PTHrP expression whereasblackarrows inf,g,j, andk point to increased Shh surrounding ectopic hair follicles. Scale bars: 200 μm; 60 μm (inset).
Figure 6
Figure 6
PTHrP promoter activation by the BMP pathway. Immortalized primary human keratinocytes were transfected in 24-well plates with PGL2Vector-LUC (1 μg), P3-Luciferase (1 μg), and P3M3 (1 μg) as indicated and grown in the presence or absence of BMP4 and Noggin proteins. Cell extracts were assayed for luciferase activity. Results shown are representative of three independent experiments, each performed in triplicate. A two-tailedt-test was performed on the data and was found to be statistically significant (*P < 0.05).
Figure 7
Figure 7
Molecules regulating the fate of ventral skin. Ventral skin can form interfollicular skin, pilosebaceous units, or nipples. The choice of cell fates lies in the balance of molecular pathway activities. The BMP pathways shown at thebottom (Msx2-independent) are from this current study. Those in thetop right (Msx2-dependent) are from Hens and colleagues. Those in thetop left are from Foley and colleagues. Gat and colleagues clarified the involvement of β-catenin along the ventral interfollicular skin to pilosebaceous unit pathway (top right) whereas Miyoshi and colleagues identified β-catenin along the nipple to pilosebaceous unit pathway (bottom right).
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