Production and processing of erythropoietin receptor transcripts in brain

The expression of erythropoietin receptor (EpoR) in brain and neuronal cells, and hypoxia-responsive production of erythropoietin (Epo) in the brain suggests that the function of Epo as a survival or viability factor may extend beyond hematopoietic tissue and erythroid progenitor cells. Epo, produced by astrocytes and neurons, can be induced by hypoxia by severalfold, and in animal models Epo administration is neuroprotective to ischemic challenge. We characterized the human EpoR transcript in brain and neuronal cells to determine its contribution in regulating the Epo response in brain. Screening of a human brain cDNA library and quantitative analysis of EpoR transcripts indicate that the EpoR gene locus is transcriptionally active in brain. In addition to the proximal promoter that is active in hematopoietic cells, a significant proportion of transcripts originates far upstream from the EpoR coding region. Unlike erythroid cells with efficient splicing of EpoR 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 and endogenous EpoR gene in hematopoietic tissue and brain. In culture of neuronal cells, hypoxia induces EpoR expression and increases sensitivity to Epo. Induction of EpoR expression appears to be a consequence of increased transcription from the upstream region and proximal promoter, and a shift towards increased processing efficiency. These data suggest that in contrast to erythropoiesis where erythroid progenitor cells express high levels of EpoR and are directly responsive to Epo stimulation, the neuroprotective effect of Epo and its receptor may require two molecular events: the induction of Epo production by hypoxia and an increase in EpoR expression in neuronal cells resulting in increased sensitivity to Epo.