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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 11 SEP 2009
Copyright © 2009 AlphaMed Press
Volume 27, Issue 12, pages 2941–2951, December 2009
How to Cite
Hughes, J. N., Dodge, N., Rathjen, P. D. and Rathjen, J. (2009), A Novel Role for γ-Secretase in the Formation of Primitive Streak-like Intermediates from ES Cells in Culture. STEM CELLS, 27: 2941–2951. doi: 10.1002/stem.218
Author contributions: J.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; N.D.: collection and/or assembly of data, data analysis and interpretation; P.R.: conception and design, financial support, administrative support, data analysis and interpretation; J.R.: conception and design, collection and/or assembly of data, data analysis and interpretation, administrative support, manuscript writing, final approval of manuscript.
First published online in STEM CELLS EXPRESS August 28, 2009.
Disclosure of potential conflicts of interest is found at the end of this article.
- Issue published online: 14 DEC 2009
- Article first published online: 11 SEP 2009
- Accepted manuscript online: 11 SEP 2009 12:00AM EST
- Manuscript Accepted: 28 AUG 2009
- Manuscript Received: 10 DEC 2008
- Australian Stem Cell Centre, Ground Floor, Building 75, STRIP, Monash University, Wellington Road, Clayton, Victoria 3800 Australia
- University of Adelaide scholarship
- Embryonic stem cell;
- Primitive streak;
γ-Secretase is a membrane-associated protease with multiple intracellular targets, a number of which have been shown to influence embryonic development and embryonic stem (ES) cell differentiation. This paper describes the use of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) to evaluate the role of γ-secretase in the differentiation of pluripotent stem cells to the germ lineages. The addition of DAPT did not prevent the formation of primitive ectoderm-like cells from ES cells in culture. In contrast, the addition of DAPT during primitive ectoderm-like cell differentiation interfered with the ability of both serum and BMP4 to induce a primitive streak-like intermediate and resulted in the preferential formation of neurectoderm. Similarly, DAPT reduced the formation of primitive streak-like intermediates from differentiating human ES cells; the culture conditions used resulted in a population enriched in human surface ectoderm. These data suggest that γ-secretase may form part of the general pathway by which mesoderm is specified within the primitive streak. The addition of an E-cadherin neutralizing antibody was able to partially reverse the effect of DAPT, suggesting that DAPT may be preventing the formation of primitive streak-like intermediates and promoting neurectoderm differentiation by stabilizing E-cadherin and preventing its proteolysis. STEM CELLS 2009;27:2941–2951