Critical role of PI3k/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF

Luis Ojeda, Junling Gao, Kristopher G. Hooten, Enyin Wang, Jason R. Thonhoff, Tiffany J. Dunn, Tianyan Gao, Ping Wu

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Article numbere23414
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - Aug 24 2011

Fingerprint

Glycogen Synthase Kinase 3
Neural Stem Cells
epidermal growth factor
Motor Neurons
Fibroblast Growth Factor 2
motor neurons
Phosphatidylinositol 3-Kinase
Stem cells
Epidermal Growth Factor
Neurons
stem cells
Fetal Stem Cells
phosphatidylinositol 3-kinase
Specifications
Chemical activation
chemical inhibitors
fibroblast growth factors
Microtubule-Associated Proteins
neurodevelopment
Fibroblast Growth Factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Critical role of PI3k/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF. / Ojeda, Luis; Gao, Junling; Hooten, Kristopher G.; Wang, Enyin; Thonhoff, Jason R.; Dunn, Tiffany J.; Gao, Tianyan; Wu, Ping.

In: PLoS One, Vol. 6, No. 8, e23414, 24.08.2011.

Research output: Contribution to journalArticle

Ojeda, Luis ; Gao, Junling ; Hooten, Kristopher G. ; Wang, Enyin ; Thonhoff, Jason R. ; Dunn, Tiffany J. ; Gao, Tianyan ; Wu, Ping. / Critical role of PI3k/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF. In: PLoS One. 2011 ; Vol. 6, No. 8.
@article{a41b9436c3ee48f685741ed888adfbd4,
title = "Critical role of PI3k/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF",
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 (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.",
author = "Luis Ojeda and Junling Gao and Hooten, {Kristopher G.} and Enyin Wang and Thonhoff, {Jason R.} and Dunn, {Tiffany J.} and Tianyan Gao and Ping Wu",
year = "2011",
month = "8",
day = "24",
doi = "10.1371/journal.pone.0023414",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Critical role of PI3k/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF

AU - Ojeda, Luis

AU - Gao, Junling

AU - Hooten, Kristopher G.

AU - Wang, Enyin

AU - Thonhoff, Jason R.

AU - Dunn, Tiffany J.

AU - Gao, Tianyan

AU - Wu, Ping

PY - 2011/8/24

Y1 - 2011/8/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80051982748&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051982748&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0023414

DO - 10.1371/journal.pone.0023414

M3 - Article

C2 - 21887250

AN - SCOPUS:80051982748

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e23414

ER -