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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1688-1695.
Prepublished online as a Blood First Edition Paper on June 3, 2004; DOI 10.1182/blood-2004-04-1247.
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Submitted April 9, 2004
Accepted May 12, 2004
Rescue of lethal c-KitW/W mice by erythropoietin
Claudia Waskow, Grzegorz Terszowski, Celine Costa, Max Gassmann, and Hans-Reimer Rodewald*
Immunology, University of Ulm, Ulm, Germany
Veterinary Physiology, University of Zuerich, Zuerich, Switzerland
* Corresponding author; email: hans-reimer.rodewald{at}medizin.uni-ulm.de.
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-KitW/W mice can be rescued by wild type hematopoietic stem cells (HSC) but it is not known whether the lethality of c-KitW/W mice is due to HSC failure or due to defects specific for erythropoiesis. Here we show that transgenic expression of erythropoietin (Epo) can overcome the lethality caused by the c-KitW/W mutation. In W-mutant mice rescued by Epo, termed "Wepo", colony forming units erythrocytes (CFU-E) 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-KitW/W mice has precluded analyses of this crucial receptor-ligand pair in adult stem/progenitor cells. Our strategy to generate viable c-KitW/W mice will be useful to analyze the role of this important receptor tyrosine kinase in adult life in vivo.

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