Critical role of PI3K/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF

• Published in: PloS one 2011-08, Vol.6 (8), p.e23414
• Main Authors: Ojeda, Luis, Gao, Junling, Hooten, Kristopher G, Wang, Enyin, Thonhoff, Jason R, Dunn, Tiffany J, Gao, Tianyan, Wu, Ping
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; AKT protein; Animals; Biology; Cell Differentiation - drug effects; Cell Lineage - drug effects; Deactivation; Diabetes; Differentiation; Dorsal horn; Enzyme Activation - drug effects; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Fetuses; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Gene Expression Regulation - drug effects; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Inactivation; Inhibition; Insulin; Kinases; Liver; Male; Microtubule-associated protein 2; Morphology; Motor neurons; Motor Neurons - cytology; Motor Neurons - drug effects; Motor Neurons - enzymology; Nervous system; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - enzymology; Neural Stem Cells - transplantation; Neurogenesis; Neurons; Neurosciences; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Phosphorylation - drug effects; Phosphoserine - metabolism; Protein Kinase C - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Ribonucleic acid; RNA; RNA Interference - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-mediated interference; Rodents; Signal Transduction - drug effects; Spinal cord injuries; Stem cell transplantation; Stem cells; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transplants & implants; Ventral horn
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023414

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 (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β 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 GSK3β enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9(+)/microtubule-associated protein 2 (MAP2)(+) motor neurons in vitro. More importantly, blocking PI3K not only enhances motor neuron differentiation from hNSCs grafted into the ventral horn of adult rat spinal cords, but also permits ectopic generation of motor neurons in the dorsal horn by overriding environmental influences. Our data suggest that FGF2 and EGF affect the motor neuron fate decision in hNSCs differently through a fine tuning of the PI3K/AKT/GSK3β pathway, and that manipulation of this pathway can enhance motor neuron generation.