The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin
Summary Neural stem cells (NSCs) can be obtained from a variety of sources, but not all NSCs exhibit the same characteristics. We have examined how the level of glycogen synthase kinase-3 activity regulates NSCs obtained from different sources: the mouse embryonic striatum, embryonic hippocampus, an...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2013-06-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/2/8/812 |
| _version_ | 1818900993572601856 |
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| author | Tamara Holowacz Tania O. Alexson Brenda L. Coles Bradley W. Doble Kevin F. Kelly James R. Woodgett Derek Van Der Kooy |
| author_facet | Tamara Holowacz Tania O. Alexson Brenda L. Coles Bradley W. Doble Kevin F. Kelly James R. Woodgett Derek Van Der Kooy |
| author_sort | Tamara Holowacz |
| collection | DOAJ |
| description | Summary
Neural stem cells (NSCs) can be obtained from a variety of sources, but not all NSCs exhibit the same characteristics. We have examined how the level of glycogen synthase kinase-3 activity regulates NSCs obtained from different sources: the mouse embryonic striatum, embryonic hippocampus, and mouse ES cells. Growth of striatal NSCs is enhanced by mild inhibition of GSK-3 but not by strong inhibition that is accompanied by Wnt/TCF transcriptional activation. In contrast, the growth of hippocampal NSCs is enhanced by both mild inhibition of GSK-3 as well as stronger inhibition. Active Wnt/TCF signaling, which occurs normally in the embryonic hippocampus, is required for growth of neural stem and progenitor cells. In the embryonic striatal germinal zone, however, TCF signaling is normally absent and its activation inhibits growth of NSCs from this region. Using a genetic model for progressive loss of GSK-3, we find that primitive ES cell-derived NSCs resemble striatal NSCs. That is, partial loss of GSK-3 alleles leads to an increase in NSCs while complete ablation of GSK-3, and activation of TCF-signaling, leads to their decline. Furthermore, expression of dominant negative TCF-4 in the GSK-3-null background was effective in blocking expression of Wnt-response genes and was also able to rescue neuronal gene expression. These results reveal that GSK-3 regulates NSCs by divergent pathways depending on the tissue of origin. The responses of these neural precursor cells may be contingent on baseline Wnt/TCF signaling occurring in a particular tissue. |
| first_indexed | 2024-12-19T20:12:41Z |
| format | Article |
| id | doaj.art-263313ab26584e0096e78d0970aa3343 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-19T20:12:41Z |
| publishDate | 2013-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-263313ab26584e0096e78d0970aa33432022-12-21T20:07:16ZengThe Company of BiologistsBiology Open2046-63902013-06-012881282110.1242/bio.2013194120131941The responses of neural stem cells to the level of GSK-3 depend on the tissue of originTamara Holowacz0Tania O. Alexson1Brenda L. Coles2Bradley W. Doble3Kevin F. Kelly4James R. Woodgett5Derek Van Der Kooy6 Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada Summary Neural stem cells (NSCs) can be obtained from a variety of sources, but not all NSCs exhibit the same characteristics. We have examined how the level of glycogen synthase kinase-3 activity regulates NSCs obtained from different sources: the mouse embryonic striatum, embryonic hippocampus, and mouse ES cells. Growth of striatal NSCs is enhanced by mild inhibition of GSK-3 but not by strong inhibition that is accompanied by Wnt/TCF transcriptional activation. In contrast, the growth of hippocampal NSCs is enhanced by both mild inhibition of GSK-3 as well as stronger inhibition. Active Wnt/TCF signaling, which occurs normally in the embryonic hippocampus, is required for growth of neural stem and progenitor cells. In the embryonic striatal germinal zone, however, TCF signaling is normally absent and its activation inhibits growth of NSCs from this region. Using a genetic model for progressive loss of GSK-3, we find that primitive ES cell-derived NSCs resemble striatal NSCs. That is, partial loss of GSK-3 alleles leads to an increase in NSCs while complete ablation of GSK-3, and activation of TCF-signaling, leads to their decline. Furthermore, expression of dominant negative TCF-4 in the GSK-3-null background was effective in blocking expression of Wnt-response genes and was also able to rescue neuronal gene expression. These results reveal that GSK-3 regulates NSCs by divergent pathways depending on the tissue of origin. The responses of these neural precursor cells may be contingent on baseline Wnt/TCF signaling occurring in a particular tissue.http://bio.biologists.org/content/2/8/812Neural stem cellsWnt signalingES cellsNeurosphere assay |
| spellingShingle | Tamara Holowacz Tania O. Alexson Brenda L. Coles Bradley W. Doble Kevin F. Kelly James R. Woodgett Derek Van Der Kooy The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin Biology Open Neural stem cells Wnt signaling ES cells Neurosphere assay |
| title | The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin |
| title_full | The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin |
| title_fullStr | The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin |
| title_full_unstemmed | The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin |
| title_short | The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin |
| title_sort | responses of neural stem cells to the level of gsk 3 depend on the tissue of origin |
| topic | Neural stem cells Wnt signaling ES cells Neurosphere assay |
| url | http://bio.biologists.org/content/2/8/812 |
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