critical role of pi3kaktgsk3β in motoneuron specification from human neural stem cells in response to fgf2 and egfpi3kaktgsk3β关键作用的运动神经元规范从人类神经干细胞fgf2和egf.pdfVIP

Critical Role of PI3K/Akt/GSK3b in Motoneuron Specification from Human Neural Stem Cells in Response to FGF2 and EGF 1.¤ 1. 2 1,3 1 Luis Ojeda , Junling Gao , Kristopher G. Hooten , Enyin Wang , Jason R. Thonhoff , Tiffany J. 1 4 1 Dunn , Tianyan Gao , Ping Wu * 1 Department of Neuroscience and Cell Biology, University Of Texas Medical Branch at Galveston, Galveston, Texas, United States of America, 2 Department of Neurosurgery, University of Florida, Gainesville, Florida, United States of America, 3 West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China, 4 Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America Abstract Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3b) activation. High levels of phosphatidylinositol 3- kinase (PI3K)/Akt activation accompanied with GSK3b inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of a constitutively active form of GSK3b enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9+/ microtubule-associated protein 2 (MAP2)+ motor neur