The mononuclear phagocyte growth factor, colony stimulating factor-1 (CSF-1), has pleiotropic roles in development and reproduction. Our studies with mice carrying a homozygous null mutation in the CSF-1 gene has shown that this growth factor is the major regulator of both the tissue density, location and function of macrophages. These studies have indicated novel roles for macrophages in the branching morphogenesis of the mammary gland and for a specialized population of macrophages, the microglia, in the brain for the establishment of a functional hypothalamic feed back loop to sex steroid hormones. In the latter case, the absence of CSF-1 signaling in female mice results in delayed puberty and a perturbed estrous cycle. In addition, the CSF-1 receptor is expressed upon trophoblastic cells in the placenta. This expression in the placenta parallels a dramatic elevation of CSF-1 synthesis in the uterus. However, CSF-1 null mutants, although reproductively severely compromised, when pregnant have normal-sized placentae. We demonstrated that this uterine CSF-1 is essential for a placental immune response to the Gram-positive bacterium, Listeria monocytogenes. CSF-1 regulates trophoblastic cells to synthesize chemokines responsible for neutrophil recruitment to the site of infection. They thus, become components of the innate immune system during pregnancy. This application seeks to extend these studies and has two specific aims: 1. Determination of the mechanistic basis of the action of microglia in establishing the sex-steroid hormone regulated feedback loop in the hypothalamus. 2. Identification of CSF-1 regulated trophoblastic functions during L. monocytogenes infection. These two aims will define signaling pathways and physiological actions of CSF-1 in two cell types that express the same cell surface CSF-1 receptor. It will cast light upon two important processes; the establishment of puberty and cyclicity in females and the regulation of placental immunity. Elucidation of these mechanisms should have profound consequences for the understanding of significant problems in women's health, menstrual cycle dysfunction, and the fetal morbidity and mortality as a result of placental infections. ? ?
Showing the most recent 10 out of 28 publications
