Epo-EpoR signaling is required during definitive hematopoiesis for the proliferation, survival, and differentiation of erythroid progenitors. In addition to its expression in hematopoietic cells, EpoR is also expressed by endothelial cells, neural cells, and cardiac tissue. But the requirement for Epo-EpoR signaling in these nonhematopoietic tissues has remained unresolved. Both Epo-and EpoR-null mouse embryos have defects in primitive hematopoiesis, cardiac formation, and blood vessel development and die between embryonic day 13 (E13) and E15 due to severe anemia. Until now, this prenatal lethality has precluded the assessment of Epo-EpoR signaling in nonhematopoietic tissues.
To address the role of EpoR signaling in nonhematopoietic cells, Suzuki and colleagues (page 2279) utilized a blood-specific regulatory element of the GATA-1 promoter to drive expression ofEpoR in the erythroid lineage of EpoR-deficient mice. Their results demonstrate that the transgenic expression ofEpoR in hematopoietic tissues was capable of rescuing viability, resulting in the birth of apparently normal, healthy, and fertile mice. Not only were the defects in primitive and definitive hematopoiesis that are normally associated with a loss of Epo signaling restored, but the rescued mice displayed normal blood vessel formation and cardiac development. Moreover, no gross neurologic symptoms were evident. These findings indicate that EpoR is not directly required for the development of the brain or cardiovascular systems, but rather the nonhematopoietic defects of Epo- and EpoR-null embryos are secondary to a lack of blood circulation.
While Epo-EpoR signaling in nonhematopoietic tissues is dispensable for viability, it remains to be determined whether there is a more subtle requirement for EpoR in their development. These mice will be invaluable for future studies aimed at investigating the role of Epo-EpoR signaling in response to stressful conditions such as hypoxia and ischemia.