Rescue of lethal c-KitW/W mice by erythropoietin.
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.
Waskow
Claudia
C
Department for Immunology, University of Ulm, D-89081 Ulm, Germany. claudia.waskow@medizin.uni-ulm.de
Terszowski
Grzegorz
G
Costa
Céline
C
Gassmann
Max
M
Rodewald
Hans-Reimer
HR
D000375:Aging / Q000502:physiology; D000740:Anemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis; D004921:Erythropoietin / Q000097:blood / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D005804:Genes, Lethal / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics
D004921:Erythropoietin; D019009:Proto-Oncogene Proteins c-kit