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.

GSK-3β Protein Phosphorylates and Stabilizes HLXB9 Protein in Insulinoma Cells to Form a Targetable Mechanism of Controlling Insulinoma Cell Proliferation

“…Consistent with our observation of reduced expression of phospho-defective HLXB9 in ␤-cells, in human fetal neural stem cells inhibition of PI3K/AKT or overexpression of active GSK-3␤ increased HLXB9 mRNA and protein expression (31), implicating that GSK-3␤-mediated phosphorylation could promote pHLXB9 stability. Also, decreased HLXB9 expression corelated with the presence of the inactive form of GSK-3␤ (31).…”

“…Also, decreased HLXB9 expression corelated with the presence of the inactive form of GSK-3␤ (31). Whether HLXB9 is phosphorylated on Ser-78/ Ser-80 in neural stem cells or in other cell types remains to be determined.…”

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

“…Due to its essential role in cell survival, the PI3K/Akt pathway and inositol phosphatases that regulate it are proposed to play a role in stem cell self-renewal, maintenance, and differentiation. This includes several types of stem cells, including pluripotent stem cells, [31,[62][63][64][65] HSC, [20,22,[66][67][68] neural stem cells [69][70][71][72][73][74], and epithelial stem cells [75]. A recurring theme in several stem cell types is for the PI3K/Akt pathway to inactivate GSK3b thus promoting activation and nuclear translocation of b-catenin [76,77].…”

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

“…Although these pathways have not previously been linked to neuromuscular pathology in SMA, β-catenin signaling pathways are known to play an important role in regulating motor neuron differentiation and stability, including regulating synaptic structure and function (42)(43)(44). Interestingly, Li and colleagues previously reported that motor neuron differentiation is regulated by retrograde signaling through β-catenin from skeletal muscle (43).…”