Exp Mol Med.  2009 Feb;41(2):116-125. 10.3858/emm.2009.41.2.014.

Bone morphogenetic protein 4 stimulates neuronal differentiation of neuronal stem cells through the ERK pathway

• Moon BS
• Yoon JY
• Kim MY
• Lee SH
• Choi T
• Choi KY

• KMID: 1109434
• DOI: http://doi.org/10.3858/emm.2009.41.2.014

Abstract

Bone morphogenic protein 4 (BMP4), a member of the TGF-beta superfamily, induced neural differentiation of neural stem cells (NSCs) grown in a medium containing basic fibroblast growth factor (bFGF). The Ras protein level and the activities of the downstream ERKs were increased by transfection of BMP4 or treatment with recombinant BMP4. The effects of BMP4, including activation of the Ras-ERK pathway and induction of the neuron marker beta-tubulin type III (Tuj1), were blocked by co-treatment of the BMP4 antagonist, noggin. The roles of the Ras-ERK pathway in neuronal differentiation by BMP4 were revealed by measuring the effect of the ERK pathway inhibition by dominant negative Ras or PD98059, the MEK specific inhibitor. BMP4 is a transcriptional target of Wnt/beta-catenin signaling, and both the mRNA and protein levels of BMP4 were increased by treatment of valproic acid (VPA), a chemical inhibitor of glycogen synthase kinase 3beta (GSK3beta) activating the Wnt/beta-catenin pathway. The BMP4- mimicking effects of VPA, activation of the Ras-ERK pathway and induction of Tuj1, also were blocked by noggin. These results indicate the potential therapeutic usage of VPA as a replacement for BMP4.

Keyword

bone morphogenetic protein 4; cell differentiation; extracellular signal-regulated MAP kinases; neurons; stem cells; valproic acid

MeSH Terms

Animals
Bone Morphogenetic Protein 4/genetics/*metabolism
Cell Differentiation/drug effects
Cells, Cultured
Cerebral Cortex/cytology/embryology
Extracellular Signal-Regulated MAP Kinases/*metabolism
Neurons/*cytology
Rats
Rats, Sprague-Dawley
Stem Cells/*cytology
Up-Regulation/drug effects
Valproic Acid/pharmacology
beta Catenin/metabolism
ras Proteins/genetics/metabolism