Neurogenin 1 mediates erythropoietin enhanced differentiation of adult neural progenitor cells.
Proneuronal basic helix-loop-helix (bHLH) transcription factor, neurogenin 1 (Ngn1), regulates neuronal differentiation during development of the cerebral cortex. Akt mediates proneuronal bHLH protein function to promote neuronal differentiation. Here, we show that recombinant human erythropoietin (rhEPO) significantly increased Akt activity and Ngn1 mRNA levels in neural progenitor cells derived from the subventricular zone (SVZ) of adult rat, which was coincident with increases of neural progenitor cell proliferation, differentiation, and neurite outgrowth. Inhibition of Akt activity by the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) inhibitor, LY294002, abolished rhEPO-increased Ngn1 mRNA levels and the effects of rhEPO on neural progenitor cells. In addition, reducing expression of endogenous Ngn1 by means of short-interfering RNA (siRNA) blocked rhEPO-enhanced neuronal differentiation and neurite outgrowth but not rhEPO-increased proliferation. Furthermore, treatment of stroke rat with rhEPO significantly increased Ngn1 mRNA levels in SVZ cells. These data suggest that rhEPO acts as an extracellular molecule that activates the PI3K/Akt pathway, which enhances adult neural progenitor cell proliferation, differentiation, and neurite outgrowth, and Ngn1 is required for Akt-mediated neuronal differentiation and neurite outgrowth.
Wang
Lei
L
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Zhang
Zheng G
ZG
Zhang
Rui L
RL
Jiao
Zhong X
ZX
Wang
Ying
Y
Pourabdollah-Nejad D
S
S
LeTourneau
Yvonne
Y
Gregg
Sara R
SR
Chopp
Michael
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004921:Erythropoietin / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016501:Neurites; D009474:Neurons / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D014157:Transcription Factors; C510879:neurogenin-1, rat