The erythropoietin (Epo) and its receptor (EpoR) system is essential for the development of the erythroid. In addition, the Epo-EpoR system was suggested to functi an in non-hematopoietic tissues, particularly in neuroprotection and angiogenesis. Howev :r, it is not clear whether the non-hematopoietic expression of EpoR is required for mammali an survival, because EpoR (-/-) mice die at around embryonic day 13 owing to a failure in erythroid cell formation. Therefore, to rescue EpoR (-/-) mice from the lethal defect in erythropoiesis, a transgene was introduced into EpoR-null mice such that they express full-length EpoR under the control of hematopoietic regulatory sequences within 1 he GATA-1 gene. We established two lines of EpoR (-/-)::EpoR transgene (+) mice; surprising y, these mice survive, develop normally and are capable of breeding. Expression of the Ep R transgene was only detectable in erythroid cells and megakaryocytes. Measurement of EpoR expression at the surface of bone marrow cells from the two rescued lines showed that EpoR expression is 120% and 40% of that of wild-type mice. Introduction of i le EpoR transgene resulted in complete rescue of both primitive and definitive hematopoieäis in EpoR-null embryos. Furthermore, rescued embryos contained as many Terll9-posit ve cells as wild-type embryos. Both lines of mice could recover from the bleeding aneir ia. Importantly, in the course of the recovery marked over-circulation of Epo was obsen ed in the line expressing a lower level of the transgene. This suggests that fewer receptors on erythroid progenitors sustained the serum level of Epo at a high level. Although t vo alternatively spliced isoforms of EpoR were reported to act as negative regulators of E x function, our results argue that these isoforms are dispensable and that only the full-len ;th EpoR is essential for normal erythropoiesis and recovery from bleeding anemia. T us study thus, unequivocally, demonstrates that non-hematopoietic expression of EpoR is unnecessary for normal mammalian survival, development, and reproduction. Accordingly, we propose that the Epo-EpoR system is critical and specific to erythropoiesis.
|Issue number||11 PART I|
|Publication status||Published - 2000 Dec 1|
ASJC Scopus subject areas
- Cell Biology