Bone morphogenetic protein 4 stimulates neuronal differentiation of neuronal stem cells through the ERK pathway.
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.
Moon
Byoung-San
BS
Department of Biotechnology and Protein Network Research Center, Yonsei University, Seoul 120-752, Korea.
Yoon
Ju-Yong
JY
Kim
Mi-Yeon
MY
Lee
Sang-Hun
SH
Choi
Thomas
T
Choi
Kang-Yell
KY
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D051176:beta Catenin; D014635:Valproic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins