CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway.
CXCL12, a ligand for the chemokine receptor CXCR4, is well known in mediating neural progenitor cell (NPC) migration during neural development. However, the effects of CXCL12 on human NPC proliferation and its associated signaling pathways remain unclear. The transcription factor, FOXO3a, a downstream target of Akt-1, is critical for cell cycle control and may also play an important role in regulating NPC proliferation. In this study, we found that CXCL12 promotes human NPC proliferation as determined by the proliferation marker Ki67 and BrdU incorporation. This CXCL12-mediated NPC proliferation was associated with an increase in Akt-1 and FOXO3a phosphorylation in a time- and dose-dependent manner. The CXCR4 antagonist (T140) or inhibitors for G proteins (Pertussis toxin) and phosphoinositide 3-kinase (PI3K) (LY294002) abolished CXCL12-mediated NPC proliferation and phosphorylation of Akt-1 and FOXO3a. The roles of Akt-1 and FOXO3a in CXCL12-mediated NPC proliferation were further investigated by using adenoviral over-expression in NPCs. Over-expression of dominant-negative Akt-1 or wild-type FOXO3a in NPC abrogated CXCL12-mediated proliferation. These data suggest that CXCL12-mediated NPC proliferation is reliant upon the phosphorylation of Akt-1 and FOXO3a and gives insight to an essential role of CXCL12 in neurogenesis. Understanding this mechanism may facilitate the development of novel therapeutic targets for NPC proliferation during neurogenesis.
Wu
Yumei
Y
Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Peng
Hui
H
Cui
Min
M
Whitney
Nicholas P
NP
Huang
Yunlong
Y
Zheng
Jialin C
JC
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D002867:Chromones; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007202:Indicators and Reagents; D009025:Morpholines; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C116977:T140 peptide; D037342:Pertussis Toxin; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins