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.
Alexander
W S
WS
Research Institute for Molecular Pathology (IMP), Vienna, Austria.
Lyman
S D
SD
Wagner
E F
EF
D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D005814:Genes, Viral; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit; D012313:RNA / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D012313:RNA; D013937:Thymidine Kinase; D019009:Proto-Oncogene Proteins c-kit