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Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression

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 ce...

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Autores principales: Ahn, Sung-Min, Byun, Kyunghee, Kim, Deokhoon, Lee, Kiyoung, Yoo, Jong Shin, Kim, Seung U., Jho, Eek-hoon, Simpson, Richard J., Lee, Bonghee
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602983/
https://www.ncbi.nlm.nih.gov/pubmed/19093005
http://dx.doi.org/10.1371/journal.pone.0003917
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author Ahn, Sung-Min
Byun, Kyunghee
Kim, Deokhoon
Lee, Kiyoung
Yoo, Jong Shin
Kim, Seung U.
Jho, Eek-hoon
Simpson, Richard J.
Lee, Bonghee
author_facet Ahn, Sung-Min
Byun, Kyunghee
Kim, Deokhoon
Lee, Kiyoung
Yoo, Jong Shin
Kim, Seung U.
Jho, Eek-hoon
Simpson, Richard J.
Lee, Bonghee
author_sort Ahn, Sung-Min
collection PubMed
description 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.
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spelling pubmed-26029832008-12-18 Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression Ahn, Sung-Min Byun, Kyunghee Kim, Deokhoon Lee, Kiyoung Yoo, Jong Shin Kim, Seung U. Jho, Eek-hoon Simpson, Richard J. Lee, Bonghee PLoS One Research Article 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. Public Library of Science 2008-12-18 /pmc/articles/PMC2602983/ /pubmed/19093005 http://dx.doi.org/10.1371/journal.pone.0003917 Text en Ahn et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ahn, Sung-Min
Byun, Kyunghee
Kim, Deokhoon
Lee, Kiyoung
Yoo, Jong Shin
Kim, Seung U.
Jho, Eek-hoon
Simpson, Richard J.
Lee, Bonghee
Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title_full Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title_fullStr Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title_full_unstemmed Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title_short Olig2-Induced Neural Stem Cell Differentiation Involves Downregulation of Wnt Signaling and Induction of Dickkopf-1 Expression
title_sort olig2-induced neural stem cell differentiation involves downregulation of wnt signaling and induction of dickkopf-1 expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602983/
https://www.ncbi.nlm.nih.gov/pubmed/19093005
http://dx.doi.org/10.1371/journal.pone.0003917
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