title: IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway.
abstract: 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.
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Yuxiu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Vasculocardiology Department, Nantong Rehibilitation Hosptital Agings, Nantong, Jiangsu, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Haoming
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Tian
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Anatomy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Jin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002867:Chromones; D005419:Flavonoids; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D050809:POU Domain Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D020032:Tyrphostins; C447031:tyrphostin AG 1024; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one