ERYTHROPOIETIN GENE-EXPRESSION IN HUMAN, MONKEY AND MURINE BRAIN

The haematopoietic growth factor erythropoietin is the primary regulat or of mammalian erythropoiesis and is produced by the kidney and the l iver in an oxygen-dependent manner. We and others have recently demons trated erythropoietin gene expression in the rodent brain. In this wor k, we show that cerebral erythropoietin gene expression is not restric ted to rodents but occurs also in the primate brain. Erythropoietin mR NA was detected in biopsies from the human hippocampus, amygdala and t emporal cortex and in various brain areas of the monkey Macaca mulatta . Exposure to a low level of oxygen led to elevated erythropoietin mRN A levels in the monkey brain, as did anaemia in the mouse brain. In ad dition, erythropoietin receptor mRNA was detected in all brain biopsie s tested from man, monkey and mouse. Analysis of primary cerebral cell s isolated from newborn mice revealed that astrocytes, but not microgl ia cells, expressed erythropoietin. When incubated at 1% oxygen, astro cytes showed >100-fold time-dependent erythropoietin mRNA accumulation , as measured with the quantitative reverse transcription-polymerase c hain reaction. The specificity of hypoxic gene induction in these cell s was confirmed by quantitative Northern blot analysis showing hypoxic up-regulation of mRNA encoding the vascular endothelial growth factor , but not of other genes. These findings demonstrate that erythropoiet in and its receptor are expressed in the brain of primates as they are in rodents, and that, at least in mice, primary astrocytes are a sour ce of cerebral erythropoietin expression which can be up-regulated by reduced oxygenation.