Production and processing of erythropoietin receptor transcripts in brain

The expression of erythropoietin receptor (EpoR) in brain and neuronal cell s, and hypoxia-responsive production of erythropoietin (Epo) in the brain s uggests that the function of Epo as a survival or viability factor may exte nd beyond hematopoietic tissue and erythroid progenitor cells. Epo, produce d by astrocytes and neurons, can be induced by hypoxia by severalfold, and in animal models Epo administration is neuroprotective to ischemic challeng e. We characterized the human EpoR transcript in brain and neuronal cells t o determine its contribution in regulating the Epo response in brain. Scree ning of a human brain cDNA library and quantitative analysis of EpoR transc ripts indicate that the EpoR gene locus is transcriptionally active in brai n. In addition to the proximal promoter that is active in hematopoietic cel ls, a significant proportion of transcripts originates far upstream from th e EpoR coding region. Unlike erythroid cells with efficient splicing of Epo R transcripts to its mature form, brain EpoR transcripts are inefficiently or alternately processed with a bias towards the 3' coding region. In human EpoR transgenic mice, anemic stress induces expression of the transgene an d endogenous EpoR gene in hematopoietic tissue and brain. In culture of neu ronal cells, hypoxia induces EpoR expression and increases sensitivity to E po. Induction of EpoR expression appears to be a consequence of increased t ranscription from the upstream region and proximal promoter, and a shift to wards increased processing efficiency. These data suggest that in contrast to erythropoiesis where erythroid progenitor cells express high levels of E poR and are directly responsive to Epo stimulation, the neuroprotective eff ect of Epo and its receptor may require two molecular events: the induction of Epo production by hypoxia and an increase in EpoR expression in neurona l cells resulting in increased sensitivity to Epo. (C) 2000 Elsevier Scienc e B.V. All rights reserved.