RESCUE OF THE PARATHYROID HORMONE-RELATED PROTEIN KNOCKOUT MOUSE DEMONSTRATES THAT PARATHYROID HORMONE-RELATED PROTEIN IS ESSENTIAL FOR MAMMARY-GLAND DEVELOPMENT

Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PT HrP is non known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory mol ecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis dur ing sexual maturity and early pregnancy now demonstrate that PTHrP pla ys a critical role in the epithelial-mesenchymal communications that g uide the initial round of branching morphogenesis that occurs during t he embryonic development of the mammary gland. We have rescued the PTH rP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary ep ithelial ducts, We show that disruption of the PTHrP gene leads to a f ailure of the initial round of branching growth that is responsible fo r transforming the mammary bud into the rudimentary mammary duct syste m, In the absence of PTHrP, the mammary epithelial cells degenerate an d disappear. The ability of PTHrP to support embryonic mammary develop ment is a function of amino-terminal PTHrP, acting via the PTH/PTHrP r eceptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expre ssion to the mammary mesenchyme using in situ hybridization histochemi stry, Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithe lial cells. We conclude that PTHrP is a critical epithelial signal rec eived by the mammary mesenchyme and involved in supporting the initiat ion of branching morphogenesis.