Expression of functional c‐kit receptors rescues the genetic defect of W mutant mast cells.

Loss‐of‐function mutations in the gene for the c‐kit tyrosine kinase receptor are strongly implicated in the developmental abnormalities of W mutant mice. To dissect further the relationship between kit and the W phenotype, retroviruses carrying the normal murine c‐kit gene were constructed. In infected cells, the level of c‐kit expression from these vectors varied markedly with different promoter elements, the 5′ viral LTR proving to be the most effective. When introduced into cells which normally do not express c‐kit, ectopic kit receptors transduced a ligand (Steel factor)‐dependent proliferative signal in IL‐3‐dependent DA‐1 myeloid cells and induced transformation in fibroblasts. Primary mutant mast cells were used to examine the effects of reconstituting functional kit expression in cells affected by W mutations. Exogenous c‐kit expression rescued the defective proliferative response to Steel factor of cells from both W/Wv and W/W mutant mice. Moreover, functional kit expression also restored the capacity of W/Wv mast cells to survive and differentiate in vivo. These results imply that defective c‐kit receptor function is sufficient to generate the W mutant phenotype.