EMBRYONIC PHAGOCYTOSIS IN MOUSE MORPHOGENESIS

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Birth defect syndromes are the leading cause of infant morbidity and mortality in the United States. Currently, only a small fraction of these syndromes are understood at the cell and molecular level. In order to understand abnormal human development investigators must characterize normal morphogenetic processes. Our long-term goals are to begin to understand the etiology of human birth defect syndromes by investigating the cell and molecular mechanisms of normal mouse development. Phase I of the physician Scientist Training program consists of basic science training through didactic coursework, laboratory rotations, and selected seminars, which will serve as the basis for a Ph. D in the Department of Biological Structure (Anatomy), University of Washington School of Medicine. The purpose of this Phase I training is to give the candidate a solid foundation in basic science in preparation for becoming an independent investigator in the fields of developmental biology and human development. Phase II of this proposal will include in depth investigation into the role of a population of phagocytic cells in normal mouse morphogenesis. Four specific aims will be used to test the hypothesis that normal mammalian development relies on a population of embryonic phagocytes, responsive to macrophage colony stimulating factor (M-CSF), for normal morphogenesis of tissues undergoing cell death and remodeling. This hypothesis will be tested with the use of immunohistochemistry and in situ hybridization to localize embryonic phagocytes, and characterized the expression patterns of M-CSF and its receptor c-fms, in four mouse strains. The strains investigated will include the M-CSF deficient op/op, and three strains with aberrant programmed cell death in regions of tissue remodeling (CL/Fr, Os/+, and Xpl). These investigations will serve to characterize the role of embryonic phagocytes, M-CSF and c-fas in normal mammalian development.