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

Byoung San Moon, Ju Yong Yoon, Mi Yeon Kim, Sang-Hun Lee, Thomas Choi, Kang Yell Choi

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Bone morphogenic protein 4 (BMP4), a member of the TGF-β 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 β-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/β-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 3β (GSK3β) activating the Wnt/β-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.

Original languageEnglish
Pages (from-to)116-125
Number of pages10
JournalExperimental and Molecular Medicine
Volume41
Issue number2
DOIs
StatePublished - 2009 Feb 28

Keywords

  • Bone morphogenetic protein 4
  • Cell differentiation
  • Extracellular signal-regulated MAP kinases
  • Neurons
  • Stem cells
  • Valproic acid

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