OVEREXPRESSION OF HUMAN STEM-CELL FACTOR IMPAIRS MELANOCYTE, MAST-CELL, AND THYMOCYTE DEVELOPMENT - A ROLE FOR RECEPTOR TYROSINE KINASE-MEDIATED MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION IN CELL-DIFFERENTIATION

Stem cell factor (SCF) is synthesized as both soluble (S) and membrane -associated (MA) proteins. Indirect insight into the function of MA an d S isoforms of SCF has come from studies performed in Steel (Sl) muta nt mice. However, the physiologic role(s) of these two isoforms remain unknown. In an attempt to better understand the in vivo role of c-kit /SCF interactions on various cell lineages, transgenic mice were gener ated that overexpress MA isoform of human SCF (hSCF). In murine cells, hSCF behaves as an antagonist to normal SCF function, due to interfer ence with the interaction between endogenous murine SCF and its recept or, c-kit, encoded by the dominant white spotting (W) gene. Mice expre ssing the hSCF transgene display a variety of phenotypic abnormalities , which are accentuated when combined with W alleles. Here we show tha t mice homozygous for the hSCF transgene demonstrate a coat color defi ciency seen in some mice homozygous for mild W alleles. Specifically, homozygous hSCF transgenic mice (hSCF(220)) display a pronounced foreh ead blaze, with additional white spots over the cervical region, as we ll as a very large belly spot. Doubly heterozygous animals that carry both a mutated Wallets and the hSCF transgene also display an unusual pigment defect and a dramatic reduction in the number of dermal mast c ells. Furthermore, overexpression of MA hSCF in the thymus results in abnormal thymocyte differentiation and proliferation, which is associa ted with reduced mitogen activated protein (MAP) kinase activation. Th us, MAP kinase activation by a receptor tyrosine kinase, such as c-kit , may be critical for the differentiation of thymocytes in vivo. (C) 1 997 by The American Society of Hematology.