In mammals there is a requirement for the development of the mother and embryo to be coordinated. This encompasses the preparation of the uterus for implantation, the development of the placenta, parturition and the development of the mammary glands in preparation for lactation. Although many of these processes are under the regulation of steroid and/or polypeptide hormones, it seems likely that their effects are mediated at least in part, by locally synthesized growth factors. Indeed, the uterus and placenta have recently been shown to be rich sources of such growth factors. This proposal is focused on one growth factor, colony stimulating factor-1 (CSF-1), which is synthesized abundantly during pregnancy by the uterine epithelium under the regulation of estradiol- 17BETA and progesterone and whose receptors, the product of the c-fms proto-oncogene, are found in oocytes, macrophages, trophoblasts and decidual cells during pregnancy. CSF-1 can be expressed as a secreted glycoprotein or proteoglycan or as a membrane spanning cell surface glycoprotein. We have shown that this growth factor plays a critical role during pregnancy because the osteopetrotic (op/op) mouse mutant which possesses an inactivating mutation in the CSF-1 gene is severely compromised in its fertility. Furthermore, op/op mice appear unable to switch to the lactational state. The overall aim of this proposal is to determine the role of CSF-1 during pregnancy. In the proposed studies extensive use will be made of the CSF-1-less op/op mouse. Specifically it is proposed to: 1) describe the pregnancy defects in op/op mice, 2) to elucidate the mechanism of hormonal regulation of uterine CSF-1 synthesis, 3) utilize transgenic approaches to determine how the glycoprotein, proteoglycan and cell surface forms of CSF-1 are involved in the regulation of events in pregnancy. These studies should provide a paradigm for the regulation of growth factor expression and function by steroid hormones. An understanding of the role of CSF-1 in pregnancy may contribute to our understanding of reproductive failures in man and the strong association of c-fms/CSF-1 expression with the progression of gynecological malignancies. In addition elucidation of the regulation of uterine macrophage populations by CSF-1 could further define the immunoregulatory role of this growth factor and may contribute to the development of approaches to combat HIV transmission during pregnancy.
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