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Molecular & Cellular Proteomics 8:585-595, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Quantitative Proteomics Characterization of a Mouse Embryonic Stem Cell Model of Down Syndrome^*,S

Yuqin Wang, Claire Mulligan, Gareth Denyer^¶, Frederic Delom, Franca Dagna-Bricarelli^||, Victor L. J. Tybulewicz^**, Elizabeth M. C. Fisher, William J. Griffiths, Dean Nizetic and Jürgen Groet^,

From the Institute of Mass-Spectrometry, School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, United Kingdom, Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London School of Medicine, Queen Mary University of London, London E1 2AT, United Kingdom, ^¶ Department of Biochemistry, University of Sydney, Sydney, Australia, ^|| Human Genetics Institute, Galliera Hospital, 16128 Genoa, Italy, ^** Medical Research Council (MRC)-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom, and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom

Down syndrome, caused by the trisomy of chromosome 21, is a complex condition characterized by a number of phenotypic features, including reduced neuron number and synaptic plasticity, early Alzheimer disease-like neurodegeneration, craniofacial dysmorphia, heart development defects, increased incidence of childhood leukemia, and powerful suppression of the incidence of most solid tumors. Mouse models replicate a number of these phenotypes. The Tc1 Down syndrome model was constructed by introducing a single supernumerary human chromosome 21 into a mouse embryonic stem cell, and it reproduces a large number of Down syndrome phenotypes including heart development defects. However, little is still known about the developmental onset of the trisomy 21-induced mechanisms behind these phenotypes or the proteins that are responsible for them. This study determined the proteomic differences that are present in undifferentiated embryonic stem cells and are caused by an additional human chromosome 21. A total of 1661 proteins were identified using two-dimensional liquid chromatography followed by tandem mass spectrometry from whole embryonic stem cell lysates. Using isobaric tags for relative and absolute quantification, we found 52 proteins that differed in expression by greater than two standard deviations from the mean when an extra human chromosome 21 was present. Of these, at least 11 have a possible functional association with a Down syndrome phenotype or a human chromosome 21-encoded gene. This study also showed that quantitative protein expression differences in embryonic stem cells can persist to adult mouse as well as reproduce in human Down syndrome fetal tissue. This indicates that changes that are determined in embryonic stem cells of Down syndrome could potentially identify proteins that are involved in phenotypes of Down syndrome, and it shows that these cell lines can be used for the purpose of studying these pathomechanisms.

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