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

Abstract

Signaling by the parathyroid hormone/parathyroid hormone-related protein receptor (Ppr) is necessary for mammary gland development beyond the early induction stage in mice. We used a series of murine models of reduced Ppr expression to determine how diminished receptor signaling influences mammary development. Reduction of Ppr expression to very low levels prevented mammary gland development. A less-severe reduction in Ppr expression permitted progression of mammary gland development beyond the induction stage, but the nipples of these mice were dramatically smaller than those of controls, with altered epidermis and connective tissue. Mothers with reduced expression of Ppr could not successfully nurse pups; however, the lactating glands did produce milk but could not efficiently deliver it. This finding was associated with reduced levels of matrix metalloproteinase-2 and an absence of pregnancy-associated remodeling of connective tissue matrix in the nipple. Reduced smooth muscle appears to underlie the majority of nipple deficiencies in mice with lower levels of the Ppr expression. Developmental Dynamics 233: 794 -803, 2005.

A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

“…However, histological analysis of mammary glands from lactating and multiparous mutant females revealed large, dilated ducts containing milk (Fig. 2D), a phenotype consistent with an inability to secrete milk (43 (Fig. 3F), as well as invagination of the epithelium into the lumen of the duct.…”

Hormone Action in the Mammary Gland

“…Intriguingly, mice lacking leptin (Lep ob /Lep ob ) or the leptin receptor (Lepr db /Lepr db ) have a rudimentary, atrophic ductal tree at 1 or 2 yr of age (Hu et al 2002). The mammary epithelium itself secretes PTHrP, important for nipple development (Kobayashi et al 2005) and prolactin that enhances mammary epithelial cell proliferation during lactation . Finally, data from humans indicate that local concentrations of 17-b-estradiol and its metabolites reflect not only serum estrogen levels but also local production resulting from conversion of C19 steroids such as androstendione and testosterone into estrogens by aromatase expressed within the gland (Santen et al 2009 and references therein) highlighting that many other factors impinge on hormone signaling.…”

Mammary glands and feathers: Comparing two skin appendages which help define novel classes during vertebrate evolution

“…Such pregnancy induced connective tissue reorganization fails to occur in the nipples of a mouse with reduced PPR expression [73]. The defective nipples of this mouse are unable to deliver milk, which is similar to the phenotype of the relaxin-null mouse [73,74].…”

“…This growth is accompanied by increased epidermal proliferation, expansion of the smooth muscle lining the primary duct and base of the nipple as well as a reorganization of collagen bundles and extracellular matrix components [50,73]. Such pregnancy induced connective tissue reorganization fails to occur in the nipples of a mouse with reduced PPR expression [73]. The defective nipples of this mouse are unable to deliver milk, which is similar to the phenotype of the relaxin-null mouse [73,74].…”

“…During pregnancy it triples in size under the influence of estrogen and relaxin [72]. This growth is accompanied by increased epidermal proliferation, expansion of the smooth muscle lining the primary duct and base of the nipple as well as a reorganization of collagen bundles and extracellular matrix components [50,73]. Such pregnancy induced connective tissue reorganization fails to occur in the nipples of a mouse with reduced PPR expression [73].…”