HEMOPOIETIC STEM CELL DIFFERENTIATION TO MACROPHAGES

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.