Conversion of the Nipple to Hair-Bearing Epithelia by Lowering Bone Morphogenetic Protein Pathway Activity at the Dermal-Epidermal Interface

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.

The evolution of milk secretion and its ancient origins

“…The development of the APSU occurs in coordinated fashion, no doubt because of crosstalk between the differentiating epithelial cells and underlying mesenchyme, as well as differences in signaling pathways and receptors of the hair follicle, apocrine gland, and sebaceous gland (Hatsell and Cowin, 2006;Andrechek et al, 2008;Mayer et al, 2008). The apocrine gland duct typically opens into the infundibulum of the hair follicle, such that secretion contacts the hair shaft.…”

“…In 2002, I hypothesized that this must be due to the inhibition of hair follicle development in the vicinity of mammary glands, and suggested that if the presumptive inhibiting compound (s) could be blocked at the earliest stages of mammary development, hair follicles may develop in association with mammary buds (Oftedal, 2002b). Although the actual signaling pathways are undoubtedly complex, with both shared and differing sensitivities to signaling compounds among different epithelial cell types, it is intriguing that bone morphogenetic proteins (BMPs) inhibit hair follicle formation, and that when Mayer et al (2008) reduced BMP signaling in the mouse by transgenic overexpression of a BMP antagonist, nipple epithelium was converted into pilosebaceous units. Mayer et al (2008) hypothesized that the BMP pathway had been co-opted during evolution of the nipple to suppress hair follicle formation.…”

“…Although the actual signaling pathways are undoubtedly complex, with both shared and differing sensitivities to signaling compounds among different epithelial cell types, it is intriguing that bone morphogenetic proteins (BMPs) inhibit hair follicle formation, and that when Mayer et al (2008) reduced BMP signaling in the mouse by transgenic overexpression of a BMP antagonist, nipple epithelium was converted into pilosebaceous units. Mayer et al (2008) hypothesized that the BMP pathway had been co-opted during evolution of the nipple to suppress hair follicle formation. If so, this occurred following the separation of marsupials and eutherians, given that hair follicle development is not suppressed during nipple development in marsupials; rather, hair follicles subsequently regress and the hairs are shed.…”

Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

“…Furthermore, inhibition of BMP signaling with the soluble antagonist Noggin can convert nipple epithelia into hair follicles (23). However, BMPR2-DN mice were found to have normal histopathology with luminal epithelial cells fully migrated to the distal tip of the fat pad (Fig.…”

Sweat Gland Progenitors in Development, Homeostasis, and Wound Repair

“…Notably, the BMP antagonist Noggin stimulates Lef1 up-regulation at the hair placode and promotes follicle formation (Botchkarev et al 1999;Jamora et al 2003). Intriguingly, transgenic mice overexpressing Noggin not only show increased hair density, but also a nearly complete substitution of eccrine glands by hair follicles in the normally hairless footpads (Plikus et al 2004) and ectopic hair follicles in the normally hairless nipple epithelium (Mayer et al 2008). These findings suggest that inhibiting BMP signaling favors hair follicle cell fates, whereas active BMP signaling promotes glandular cell fates.…”