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.
Highlights
Understanding the mechanism of the differentiation of neuronal stem cells (NSCs) in the central nervous system (CNS) is important in the field of regenerative medicine
The NSCs underwent morphological differentiation when the cells were treated with Bone morphogenic protein 4 (BMP4), which differentiation was inhibited by co-treatment of the BMP4 antagonist, noggin (Figure 1A)
The differentiation of NSCs by BMP4 and the blocking of the effect by noggin were confirmed by immunocytochemical analysis using the neuronal marker β-tubulin type III (Tuj1)
Summary
Understanding the mechanism of the differentiation of neuronal stem cells (NSCs) in the central nervous system (CNS) is important in the field of regenerative medicine. The expressions of the extracellular secretory factors play significant roles in the differentiation of multipotent stem cells (Panchision and McKay, 2002; Jung et al, 2007). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, are extracellular secretory proteins effecting neuronal differentiation (Varley and Maxwell, 1996; Li et al, 1998). Involvement of several signaling pathways such as Wnt/βcatenin, Phosphoinositide-3 kinase (PI-3K), p38, ERK and JNK in the proliferation and differentiation of mouse embryonic stem cells was indicated without characterization of mechanisms (Lin et al, 2008). Involvement of other signaling pathway (s) in BMP4's neuronal differentiation of NSCs remains unclear
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