Hemopoietic Stem Cell Differentiation to Macrophages

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DESCRIPTION (provided by applicant): Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiation of mononuclear phagocytes, including tissue macrophages and osteoclasts, that play critical roles in the development and function of the tissues in which they reside. CSF-1 is also important in fertility, regulating testicular macrophages and cells of the female reproductive tract, including decidual cells, trophoblast, oocytes, embryonic cells and macrophages. Not surprisingly, therefore, CSF-1-nullizygous Csf1op/Csf1op mice have a pleiotropic phenotype. Local production of CSF-1 contributes to the local accumulation of macrophages in chronic inflammatory diseases, such as arthritis and autoimmune glomerular nephritis. In addition, CSF-1 has important autocrine and/or paracrine roles in neoplasias of the myeloid, lymphoid and female reproductive systems. CSF-1 is either secreted as a glycoprotein or chondroitin sulfate-containing proteoglycan, both of which are found in biologically active concentrations in the circulation, or expressed as a biologically active membrane-spanning glycoprotein. The cell surface CSF-1 and the proteoglycan CSF-1 can act in a localized fashion, the former by direct cell-cell interaction with target cells or by local proteolytic release of soluble growth factor from the cell surface, and the proteoglycan CSF-1 by its sequestration to particular extracellular matrices. Elucidation of the sites of local CSF-1 synthesis and of accumulation of tissue macrophages have suggested paradigms for the function of these CSF-1 isoforms in physiology and disease that can be studied in recently developed mouse model systems. The effects of CSF-1 are mediated via the CSF-1 receptor (CSF-1 R), an approximately 165-kDa tyrosine kinase encoded by the c-fms protooncogene. The phenotype of CSF-1R-nullizygous mice is more severe than the phenotype of CSF-1-nullizygous mice. Thus, while all of the effects of CSF-1 are mediated by this receptor, other effects may be mediated by CSF-1 -independent CSF-1 R activation. The overall aim of the proposal is to utilize recently developed, novel mouse model systems to understand the roles of CSF-1 and the CSF-1 R in development and disease. The specific aims are: 1. To analyze the role of CSF-1 isoforms in development and disease. 2. To determine the consequences of inappropriate autocrine regulation by CSF-1. 3. To elucidate the basis of the difference in phenotype between CSF-1 - and CSF-1 R-nullizygous mice. 4. To identify CSF-1 R mutations regulating mononuclear phagocyte commitment and differentiation.