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A novel role for gamma-secretase in the formation of primitive streak-like intermediates from ES cells in culture


Hughes, JN and Dodge, N and Rathjen, PD and Rathjen, J, A novel role for gamma-secretase in the formation of primitive streak-like intermediates from ES cells in culture, Stem Cells: Reporting on Clinical and Experimental Research in The Field of Progenitor Cell Differentiation and Proliferation, 27, (12) pp. 2941-2951. ISSN 1066-5099 (2009) [Refereed Article]

DOI: doi:10.1002/stem.218


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 c-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 c-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. © AlphaMed Press.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell development, proliferation and death
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Rathjen, PD (Professor Peter Rathjen)
UTAS Author:Rathjen, J (Dr Joy Rathjen)
ID Code:78727
Year Published:2009
Web of Science® Times Cited:20
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-07-24
Last Modified:2012-07-24

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