Erythropoietin receptor spliced forms differentially expressed in blind subterranean mole rats

Erythropoietin (Epo) is the primary regulator of erythropoiesis, controlling the proliferation, maturation, and survival of erythroid progenitor cells. The functions of Epo are mediated through its specific receptor (EpoR) expressed mainly on the surface of erythroid progenitor cells, and the expression of both responds to hypoxia. The subterranean mole rat (Spalax) is a unique model system to study the molecular mechanisms for adaptation to hypoxia. Here, we cloned two forms of Spalax EpoR: a complete EpoR cDNA as well as a novel truncated bone marrow specific EpoR form. In the full-length Spalax EpoR (sEpoR), two out of the eight conserved tyrosine- phosphorylation sites were substituted (Y481F and Y499G), suggesting that Spalax Epo signaling pathways may be modulated. The level of the sEpoR mRNA in the spleen and in bone marrow was relatively low and similar in Spalax newborns and adults, with no significant response to hypoxia. The truncated sEpoR was not detected in the spleen and comprised only approximately 1% of the sEpoR expressed in the bone marrow. In Rattus, the truncated EpoR form was approximately 15% of the total expressed receptor. The level of Rattus EpoR in newborn spleens was three- to fourfold higher than in Spalax newborns and decreased toward adulthood. Severe hypoxia induces a significant increase in adult Rattus EpoR. Our data provide further insight into the adaptive mechanisms of Spalax to the extreme conditions of hypoxia in its subterranean environment.