Mononuclear phagocytic cells comprise bone marrow progenitor cells, blood monocytes and tissue macrophages. The growth factor, colony stimulating factor-1 (CSF-1), humorally regulates mononuclear phagocytes and locally regulates placental function. Interestingly, CSF-1 can be either expressed on the cell surface or rapidly secreted from cells. The overall aim of this project is to study how CSF-1 locally and humorally regulates target cells in the mouse and in lower organisms with highly developed genetics. In the mouse, this aim will be addressed by studying a mouse mutant which totally lacks CSF-1 due to an inactivating mutation in the CSF-1 gene. It is proposed to define those situations in which CSF-1 is acting at a distance and those in which it is acting locally and, if locally, whether this action requires cell-cell contact between CSF-1-producing and CSF-1- responding cells. Experiments will involve attempts to reconstitute the mutant mice by administration of CSF-1 or transgenically, using constructs expressing different forms of CSF-1. Other experiments with this mouse and normal mice will be directed towards understanding the role of CSF-1 in primitive hemopoietic cell production. In addition, it is proposed to clone the genes for the CSF-1R in and its ligand in Drosophila and Caenorhabditis elegans in order to compare and contrast the roles of the receptor and its ligand in these organisms with their roles in mammalian systems, as well as to develop genetic approaches for the analysis of CSF-1 signal transduction pathways and for the regulation of CSF-1 expression.
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