Nipple connective tissue and its development: insights from the K14-PTHrP mouse

Abstract

Parathyroid hormone-related protein (PTHrP) regulates a wide variety of developmental processes. Keratin 14 (K14) promoter-mediated overexpression of PTHrP in the epidermis during development converts the entire murine ventral skin to hairless nipple-like skin. In this report, we characterize the morphology and processes that influence the development of nipple connective tissue. The connective tissue of the nipple displayed increased levels of proteoglycans, and collagen bundles with atypical morphology, as well as increased numbers of mast cells, capillaries, nerve fibers and dermal melanocytes. The unique characteristics of nipple connective tissue were not present until mice reach 3-4 weeks of age. The adult male K14-PTHrP mouse has a less dramatic ventral skin phenotype, and does not manifest a nipple-like dermis. Ovariectomy or orchiedectomy prior to sexual maturity had no impact on the ventral skin of the male or female K14-PTHrP mice, but exposure to androgens in utero repressed many of the nipple-like characteristics in the ventral skin of the female K14-PTHrP mice.

Reduced expression of the PTH/PTHrP receptor during development of the mammary gland influences the function of the nipple during lactation

“…It has long been recognized that the rise of androgens in the murine male fetus triggers the dense mammary mesenchyme to constrict around and destroy the mammary epithelium (reviewed in Sakakura, 1987). However, as the mammary bud is being destroyed, the fibroblasts of the dense mammary mesenchyme also undergo apoptosis and are removed from the developing ventral dermis (Dunbar, 1999;Abdalkhani et al, 2002). Accordingly, in the male K14-PTHrP mouse (as well as female transgenics treated in utero with androgens), the ectopic dense mammary mesenchyme is removed by apoptosis and the ventral skin lacks many of the cellular and extracellular matrix attributes of nipple connective tissue (Abdalkhani et al, 2002).…”

“…However, as the mammary bud is being destroyed, the fibroblasts of the dense mammary mesenchyme also undergo apoptosis and are removed from the developing ventral dermis (Dunbar, 1999;Abdalkhani et al, 2002). Accordingly, in the male K14-PTHrP mouse (as well as female transgenics treated in utero with androgens), the ectopic dense mammary mesenchyme is removed by apoptosis and the ventral skin lacks many of the cellular and extracellular matrix attributes of nipple connective tissue (Abdalkhani et al, 2002). The question remains as to how the dense mammary mesenchyme influences the formation of nipple connective tissue in females.…”

“…Additional evidence for a role of PTHrP-Ppr signaling in the generation of the nipple comes from transgenic mice in which the human keratin 14 (K14) cassette drives overexpression of PTHrP . These mice displayed a hairless wrinkled ventral skin that shared several morphological characteristics with the murine nipple Foley et al, 2001;Abdalkhani et al, 2002). It appeared that the nipple-like skin phenotype of the K14-PTHrP mouse resulted from the expression of PTHrP within the developing epidermis, leading to the ectopic acquisition of the mammary mesenchyme fate by the entire ventral dermis (Dunbar et al, 1999;Foley et al, 2001).…”

“…The epidermis of the nipple contains expanded suprabasal and granular layers in comparison to those of dorsal or ventral murine skin (Foley et al, 2001;unpublished observations). Nipple connective tissue differs from surrounding dermis in that it contains smaller, more-irregular collagen bundles, increased glycosaminoglycan content, capillaries, nerve fibers, and mast cells, as well as unique elements such as smooth muscle beds and dermal melanocytes (Abdalkhani et al, 2002). Thus, a major consequence of PTHrP-Ppr signaling in the developing mammary gland is the formation of the nipple.…”

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

“…However, other factors such as timing of transgene expression or sensitivity of somatic versus lateral plate-derived mesenchymal cells to PTHrP may be involved (Foley et al, 2001). In the adult female mouse, the ectopic expression of PTHrP results in a hairless skin with a thickened epidermis and complex connective tissue consistent with the nipple (Abdalkhani et al, 2002;Foley et al, 2001Foley et al, , 1998. Whether the fibroblasts that underlie the nipple are simply derived from mammary mesenchyme cells remains to be determined.…”