Erythropoietin is known for its role in erythropoiesis and acts by binding to its receptor on the surface of erythroid progenitors. Erythropoietin receptor expression follows the site of hematopoiesis from the embryonic yolk sac to the fetal liver, and then the adult spleen and bone marrow. However, expression of the erythropoietin receptor has also been observed in select cells of non-hematopoietic origin such as vascular endothelium. We also observed erythropoietin receptor expression in the embryonic mouse brain during mid-gestation which is developmentally regulated and falls to very low levels by birth. Erythropoietin receptor transcripts in the brain appear to be alternatively processed suggesting that both transcription and post-transcriptional RNA processing play an important role in regulating the level of erythropoietin receptor expression particularly in the adult brain. The expression pattern of beta-galactosidase reporter gene in transgenic mouse embryos suggested that the human erythropoietin receptor promoter region between - 1778 bp and - 150 bp 5' of the transcription start site contains regulatory sequences to direct erythropoietin receptor expression in the neural tube at embryonic day 9.5. A transgene containing the complete human erythropoietin receptor gene including this promoter fragment provides a low level of hematopoietic specific expression as well as a constant low level in the brain suggesting that the promoter fragment extending to - 1778bp is necessary but not sufficient to provide complete developmental control of erythropoietin receptor expression in hematopoietic tissue or brain. Using a larger 80kb human transgene with an additional 4kb of 5' flanking sequence, we recapitulated the high level erythropoietin receptor expression in hematopoietic tissue as well as the pattern of developmental expression in brain. These data demonstrate that both the mouse and human erythropoietin receptor genes contain regulatory elements to direct significant levels of expression in a developmentally controlled manner in both hematopoietically active tissue and brain and suggest that in addition to its function during erythropoiesis, EpoR may play a role in the development of select non-hematopoietic tissue.
