IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway

• Published in: PloS one Vol. 9; no. 12; p. e113801
• Main Authors: Zhang, Xinhua, Zhang, Lei, Cheng, Xiang, Guo, Yuxiu, Sun, Xiaohui, Chen, Geng, Li, Haoming, Li, Pengcheng, Lu, Xiaohui, Tian, Meiling, Qin, Jianbing, Zhou, Hui, Jin, Guohua
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.12.2014; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Biology and Life Sciences; Brain-derived neurotrophic factor; Cell differentiation; Cell Differentiation - drug effects; Cells, Cultured; Chromones - pharmacology; Denervation; Differentiation (biology); Female; Flavonoids - pharmacology; Growth factors; Hippocampus; Hippocampus - cytology; Inhibitors; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Kinases; MAP kinase; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Morpholines - pharmacology; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurons; Neurosciences; Pathways; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; POU Domain Factors - genetics; POU Domain Factors - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; Stem cells; Surgery; TOR protein; Tyrphostins - pharmacology; Up-Regulation - drug effects; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113801

Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs) in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1) in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002), but not MAPK inhibitor (PD98059); levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024) and mTOR (rapamycin) both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways.