THE C-KIT RECEPTOR, STEM-CELL FACTOR, AND MAST-CELLS - WHAT EACH IS TEACHING US ABOUT THE OTHERS

Many years ago, alert observers noticed among thousands of laboratory mice a few individuals that, unlike their littermates, exhibited areas of white spotting on their fur. No one could have predicted then that an effort to understand the basis for these abnormalities would ultim ately contribute to the characterization of a receptor (c-kit) and a c orresponding ligand (stem cell factor, SCF) that are critical not only to the migration and development of melanocytes, but also to hematopo iesis, gametogenesis, mast cell development, and, perhaps, development of the central nervous system. Nor could anyone have foretold then th at this receptor and ligand would be shown to regulate the development of multiple distinct cellular lineages not only in mice, but also in humans and other primates, or that c- kit and its ligand would be foun d to influence the secretory function of cells bearing this receptor, as well as their development. Investigation of the effects of SCF on a single cell type, the mast cell, has produced the most complete pictu re of the spectrum of biological processes that can be regulated by in teractions between c-kit and its ligand. This work shows that SCF crit ically regulates the migration and survival of mast cell precursors, p romotes the proliferation of both immature and mature mast cells, enha nces mast cell maturation, directly induces secretion of mast cell med iators, and can regulate the extent of mediator release in mast cells activated by IgE-dependent mechanisms. Indeed, SCF may well prove to b e one of the most important of the factors influencing mast cell numbe rs, phenotype, and function in both health and disease. It now seems v irtually certain that further studies of c-kit and SCF will produce im portant new insights into problems as diverse as the regulation of lin eage commitment during normal hematopoiesis or the development and fun ction of the central nervous system. And even though an effect on mast cell development was one of the last phenotypic abnormalities to be r ecognized in mice with mutations affecting the genes encoding c-kit or SCF, mast cells will continue to represent an important model system for analyzing the biology of c-kit and its ligand.