Rescue of lethal c-KitW/W mice by erythropoietin

Blood. 2004 Sep 15;104(6):1688-95. doi: 10.1182/blood-2004-04-1247. Epub 2004 Jun 3.


Homozygous natural white-spotted (W) mutations in the gene encoding the receptor tyrosine kinase c-Kit are associated with hypoplastic bone marrow, severe macrocytic anemia, and lethality during early postnatal life. c-Kit(W/W) mice can be rescued by wild-type hematopoietic stem cells (HSCs), but it is not known whether the lethality of c-Kit(W/W) mice is the result of HSC failure or defects specific for erythropoiesis. Here we show that transgenic expression of erythropoietin (EPO) can overcome the lethality caused by the c-Kit(W/W) mutation. In W mutant mice rescued by EPO, termed WEPO, erythrocyte colony-forming units (CFU-Es) are rescued to normal frequencies. Hence, Epo receptor signals can partially bypass the strict requirement for c-Kit signaling in erythropoiesis in the absence of c-Kit in vivo. Using a series of W and rescue mouse strains, we define here the erythropoietic threshold permitting survival in vivo. The lethality of c-Kit(W/W) mice has precluded analysis of this crucial receptor-ligand pair in adult stem/progenitor cells. Our strategy to generate viable c-Kit(W/W) mice will be useful to analyze the role of this important receptor tyrosine kinase in adult life in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology
  • Anemia / genetics
  • Anemia / pathology
  • Anemia / physiopathology
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Membrane / metabolism
  • Cell Survival
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Erythroid Precursor Cells / metabolism
  • Erythroid Precursor Cells / pathology
  • Erythropoiesis
  • Erythropoietin / blood
  • Erythropoietin / genetics*
  • Erythropoietin / metabolism*
  • Erythropoietin / pharmacology
  • Gene Expression Regulation
  • Genes, Lethal / genetics*
  • Genotype
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation / genetics*
  • Proto-Oncogene Proteins c-kit / analysis
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Spleen / drug effects
  • Spleen / metabolism
  • Survival Rate
  • Transgenes / genetics


  • Erythropoietin
  • Proto-Oncogene Proteins c-kit