BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction

Abstract

The mammary glands develop initially as buds arising from the ventral embryonic epidermis. Recent work has shed light on signaling pathways leading to the patterning and formation of the mammary placodes and buds in mouse embryos. Relatively little is known of the signaling pathways that initiate branching morphogenesis and the formation of the ducts from the embryonic buds. Previous studies have shown that parathyroid hormone-related protein (PTHrP; also known as parathyroid hormone-like peptide, Pthlh) is produced by mammary epithelial cells and acts on surrounding mesenchymal cells to promote their differentiation into a mammary-specific dense mesenchyme. As a result of PTHrP signaling, the mammary mesenchyme supports mammary epithelial cell fate, initiates ductal development and patterns the overlying nipple sheath. In this report, we demonstrate that PTHrP acts, in part, by sensitizing mesenchymal cells to BMP signaling. PTHrP upregulates BMP receptor 1A expression in the mammary mesenchyme, enabling it to respond to BMP4, which is expressed within mesenchymal cells underlying the ventral epidermis during mammary bud formation. We demonstrate that BMP signaling is important for outgrowth of normal mammary buds and that BMP4 can rescue outgrowth of PTHrP -/-mammary buds. In addition, the combination of PTHrP and BMP signaling is responsible for upregulating Msx2 gene expression within the mammary mesenchyme, and disruption of the Msx2 gene rescues the induction of hair follicles on the ventral surface of mice overexpressing PTHrP in keratinocytes (K14-PTHrP). Our data suggest that PTHrP signaling sensitizes the mammary mesenchyme to the actions of BMP4, triggering outgrowth of the mammary buds and inducing MSX2 expression, which, in turn, leads to lateral inhibition of hair follicle formation within the developing nipple sheath.

Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme

“…Conversely, transgenic overexpression of PTHrP in the basal epidermis (under control of the keratin 14 promoter, K14-PTHrP mice) leads to conversion of the ventral dermis into mammary mesenchyme, suppression of hair follicle development and differentiation of the entire ventral surface into nipple-sheath epidermis (Foley et al, 2001). These and other results have demonstrated that PTHrP signals from the mammary bud epithelium to the mesenchyme to induce the proper differentiation of the specialized mammary mesenchyme, which, in turn, supports further epithelial morphogenesis (Hens et al, 2007;Cowin and Wysolmerski, 2010).…”

Ptch1is required locally for mammary gland morphogenesis and systemically for ductal elongation

“…Induction of the milk line and mammary placodes requires inductive tissue interactions from somites, as well as from a mesodermally derived mammary mesenchyme, to an overlying ectodermally derived epithelium (Chu et al, 2004;Sakakura, 1987;Veltmaat et al, 2003;Veltmaat et al, 2006). Between ~E12 and ~E16, the mammary gland consists of a small bulb of epithelium that begins to invade the fat pad precursor mesenchyme (which gives rise to the mammary fat pad stroma in the postnatal animal) (Hens et al, 2007;Sternlicht, 2006). This early gland development is hormone-independent.…”

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

“…However, this has minimal impact on cells of the dorsal dermis (Foley et al, 2001). In part, this appears to be the result of increased Bmp4 signaling in the developing ventral skin of the embryo, driving mammary mesenchyme differentiation (Hens et al, 2007). 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).…”