1. Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
- Author
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Eek-hoon Jho, Richard J. Simpson, Sung-Min Ahn, Seung U. Kim, Kyunghee Byun, Bonghee Lee, Jong Shin Yoo, Deokhoon Kim, and Kiyoung Lee
- Subjects
Cellular differentiation ,medicine.medical_treatment ,Neurogenesis ,lcsh:Medicine ,Down-Regulation ,Nerve Tissue Proteins ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Neurosphere ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Tissue Distribution ,Phosphorylation ,lcsh:Science ,Cells, Cultured ,beta Catenin ,030304 developmental biology ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Neurons ,0303 health sciences ,Induced stem cells ,Multidisciplinary ,Gene Expression Profiling ,Stem Cells ,lcsh:R ,Wnt signaling pathway ,Cell Differentiation ,Stem-cell therapy ,Oligodendrocyte Transcription Factor 2 ,Neural stem cell ,3. Good health ,Cell biology ,Developmental Biology/Stem Cells ,Developmental Biology/Neurodevelopment ,Wnt Proteins ,Developmental Biology/Cell Differentiation ,Intercellular Signaling Peptides and Proteins ,lcsh:Q ,Stem cell ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction - Abstract
Understanding stem cell-differentiation at the molecular level is important for clinical applications of stem cells and for finding new therapeutic approaches in the context of cancer stem cells. To investigate genome-wide changes involved in differentiation, we have used immortalized neural stem cell (NSC) line (HB1.F3) and Olig2-induced NSC differentiation model (F3.Olig2). Using microarray analysis, we revealed that Olig2-induced NSC differentiation involves downregulation of Wnt pathway, which was further confirmed by TOPflash/FOPflash reporter assay, RT-PCR analysis, immunoblots, and immunocytochemistry. Furthermore, we found that Olig2-induced differentiation induces the expression of Dickkopf-1(Dkk1), a potent antagonist of Wnt signaling. Dkk1 treatment blocked Wnt signaling in HB1.F3 in a dosage-dependent manner, and induced differentiation into astrocytes, oligodendrocytes, and neurons. Our results support cancer stem cell hypothesis which implies that signaling pathway for self-renewal and proliferation of stem cells is maintained till the late stage of differentiation. In our proposed model, Dkk1 may play an important role in downregulating self-renewal and proliferation pathway of stem cells at the late stage of differentiation, and its failure may lead to carcinogenesis.
- Published
- 2008