Roles of colony stimulating factor -1 in mammary gland development and transforming growth factor-beta3 in mammary gland involution
Nguyen, Anh (Andrew) Van
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Colony Stimulating Factor-1 (CSF-1) is a growth factor that regulates macrophage growth and differentiation. Osteopetrotic mice (csfm op/csfmop) carry a null mutation in the gene encoding for the CSF-1 and hence, have a paucity of macrophages in many tissues. These mice exhibit many abnormalities including a lack of sex steroid hormone negative feedback control to the hypothalamus-pituitary axis, an extended estrous cycle, and a poor ductal branching in the mammary glands suggesting that macrophages play a major role in these tissues. To address specifically the role of macrophages in the mammary gland, we have used a tetracycline binary system to express CSF-1 specifically in this tissue. We have shown that CSF-1 is locally produced in the mammary gland using the mouse mammary tumor virus promoter/enhancer driving the expression of the transactivator (MMTV-tTA), which when present activates the expression from the tetracycline responding element (tetop-CSF-1). Local production of CSF-1 in the mammary glands recruits macrophages to the area around the terminal end buds. This was associated with a partial rescue of the ductal defect in the mammary glands of the osteopetrotic mice.;The Transforming Growth Factor-beta (TGF-beta) family has been shown to inhibit mammary ductal outgrowth. Initially, we hypothesize that one of these members of this growth factor family could mediate the action of CSF-1 in the mammary glands of the osteopetrotic mice since these mice fail to develop normal ductal tree. We have found that TGF-beta3 but not TGF-beta1 or TGF-beta2 is up regulated in the mammary gland of the osteopetrotic mice but not in the wild type gland during the early lactation period. We have shown that TGF-beta3 production is regulated by the local environment, such as the milk stasis and not by a drop in systemic lactogenic hormones. Mice expressed TGF-beta3 transgene from the beta-lactoglobulin promoter exhibited numerous apoptotic cells in a pattern similar to that observed in involuting mammary glands. Transplantation of neonatal mammary tissue derived from TGF-beta3 null mutant mice into syngenic hosts resulted in a significant inhibition of cell death compared to wild type mice upon milk stasis. These results provide direct evidence that TGF-beta3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.