Journal
DEVELOPMENT GROWTH & DIFFERENTIATION
Volume 48, Issue 8, Pages 513-523Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1440-169x.2006.00889.x
Keywords
embryonic stem cell; extracellular signal-regulated kinase (ERK) phosphorylation; growth factor; neurite outgrowth; neuronal differentiation
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Funding
- NCRR NIH HHS [C06 RR015455] Funding Source: Medline
- NINDS NIH HHS [NS045155, NS045810] Funding Source: Medline
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Embryonic stem (ES) cells represent an ideal source for cell engraftment in the damaged central nervous system (CNS). Understanding key signals that control ES cell differentiation may improve cell type-specific differentiation that is suitable for transplantation therapy. We tested the hypothesis that extracellular signal-regulated kinase (ERK) 1/2 phosphorylation is an early signaling event required for the neuronal differentiation of ES cells. Cultured mouse ES cells were treated with an all-trans-retinoic-acid (RA) protocol to generate neurally induced progenitor cells. Western blot analysis showed a dramatic increase in ERK 1/2 phosphorylation (p-ERK 1/2) 1-5 days after RA induction, which was attenuated in the presence of the p-ERK 1/2-specific inhibitor UO126. Phospho-ERK 1/2 inhibition significantly reduced the number of NeuN-positive cells and the expression of associated cytoskeletal proteins. In differentiating ES cells, there was increased nuclear translocation of STAT3 and decreased protein expression levels of GDNF, BDNF and NGF. STAT3 translocation was attenuated by UO126. Finally, caspase-3 activation was observed in the presence of UO126, suggesting that the ERK pathway also contributes to the survival of differentiating ES cells. These data indicate that ERK 1/2 phosphorylation is a key event required for early neuronal differentiation and survival of ES cells.
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