Lactational competence and involution of the mouse mammary gland require plasminogen

Urokinase-type plasminogen activator expression is induced in the mouse mam mary gland during development and post-lactational involution, We now show that primiparous plasminogen-deficient (Plg(-/-)) mice have seriously compr omised mammary gland development and involution. All mammary glands were un derdeveloped and one-quarter of the mice failed to lactate. Although the gl ands from lactating Plg(-/-) mice were initially smaller, they failed to in volute after weaning, and in most cases they failed to support a second lit ter. Alveolar regression was markedly reduced and a fibrotic stroma accumul ated in Plg(-/-) mice. Nevertheless, urokinase and matrix metalloproteinase s (MMPs) were upregulated normally in involuting glands of Plg-/- mice, and fibrin did not accumulate in the glands. Heterozygous Plg(+/-) mice exhibi ted haploinsufficiency, with a definite, but less severe mammary phenotype. These data demonstrate a critical, dose-dependent requirement for Plg in l actational differentiation and mammary gland remodeling during involution.