Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells.
Recent studies have shown that neurogenesis is enhanced after hypoxia and that erythropoietin (EPO), an inducible cytokine, is produced in the brain as part of the intrinsic hypoxia response. Thus, we asked whether EPO might regulate neurogenesis by forebrain neural stem cells (NSCs). We found that EPO receptors are expressed in the embryonic germinal zone during neurogenesis as well as in the adult subventricular zone, which continues to generate neurons throughout adulthood. Cultured NSCs exposed to a modest hypoxia produced two- to threefold more neurons, which was associated with an elevation in EPO gene expression. The enhanced neuron production attributable to hypoxia was mimicked by EPO and blocked by coadministration of an EPO neutralizing antibody. EPO appears to act directly on NSCs, promoting the production of neuronal progenitors at the expense of multipotent progenitors. EPO infusion into the adult lateral ventricles resulted in a decrease in the numbers of NSCs in the subventricular zone, an increase in newly generated cells migrating to the olfactory bulb, and an increase in new olfactory bulb interneurons. Infusion of anti-EPO antibodies had the opposite effect: an increase in the number of NSCs in the subventricular zone and a decrease in the number of newly generated cells migrating to the bulb. These findings suggest that EPO is an autocrine-paracrine factor, capable of regulating the production of neuronal progenitor cells by forebrain NSCs.
Shingo
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Genes & Development Research Group, Department of Cell Biology and Anatomy, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1.
Sorokan
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Shimazaki
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Weiss
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D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007276:Injections, Intraventricular; D007395:Interneurons / Q000166:cytology / Q000187:drug effects; D020547:Lateral Ventricles / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects; D019899:Paracrine Communication / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis
D000906:Antibodies; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D004921:Erythropoietin; D016328:NF-kappa B; D010455:Peptides; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C118258:SN50 peptide