A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery.
Erythropoietin (EPO) is the principal growth factor regulating the production of red blood cells. Recent studies demonstrated that exogenous EPO acts as a neuroprotectant and regulates neurogenesis. Using a genetic approach, we evaluate the roles of endogenous EPO and its classical receptor (EPOR) in mammalian neurogenesis. We demonstrate severe and identical embryonic neurogenesis defects in animals null for either the Epo or EpoR gene, suggesting that the classical EPOR is essential for EPO action during embryonic neurogenesis. Furthermore, by generating conditional EpoR knock-down animals, we demonstrate that brain-specific deletion of EpoR leads to significantly reduced cell proliferation in the subventricular zone and impaired post-stroke neurogenesis. EpoR conditional knockdown leads to a specific deficit in post-stroke neurogenesis through impaired migration of neuroblasts to the peri-infarct cortex. Our results suggest that both EPO and EPOR are essential for early embryonic neural development and that the classical EPOR is important for adult neurogenesis and for migration of regenerating neurons during post-injury recovery.
Tsai
Peter T
PT
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
Ohab
John J
JJ
Kertesz
Nathalie
N
Groszer
Matthias
M
Matter
Cheryl
C
Gao
Jing
J
Liu
Xin
X
Wu
Hong
H
Carmichael
S Thomas
ST
D000818:Animals; D001921:Brain / Q000196:embryology* / Q000503:physiopathology*; D002455:Cell Division; D019070:Cell Lineage; D004261:DNA Replication; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology*; D019426:Integrases; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology; D009432:Neural Crest / Q000166:cytology; D009436:Neural Tube Defects / Q000235:genetics; D046569:Neuroepithelial Cells / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D014764:Viral Proteins
D009419:Nerve Tissue Proteins; D017467:Receptors, Erythropoietin; D014764:Viral Proteins; D004921:Erythropoietin; C045073:Cre recombinase; D019426:Integrases