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Quantitative proteomics characterization of a mouse embryonic stem cell model of Down syndrome.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC2667343 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Quantitative proteomics characterization of a mouse embryonic stem cell model of Down syndrome.

Wang Yuqin Y Mulligan Claire C Denyer Gareth G Delom Frederic F Dagna-Bricarelli Franca F Tybulewicz Victor L J VL Fisher Elizabeth M C EM Griffiths William J WJ Nizetic Dean D Groet Jürgen J

Molecular & cellular proteomics : MCP 20081110 4

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 introduc ...[more]

PMID: 19001410

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Project description:OBJECTIVE:To estimate whether prenatal treatment with neuroprotective peptides prevents the developmental delay and the glial deficit in the Ts65Dn mouse model for Down syndrome and to explore the peptides' effects on achievement of normal development. METHODS:Pregnant Ts65Dn females were randomly assigned to NAPVSIPQ+SALLRSIPA or control and were treated by investigators blinded to treatment and genotype on gestational days 8-12. Offspring were tested from postnatal day 5 to 21 for motor and sensory milestones with standardized tests by operators blinded to the pup's treatment and genotype. The pup's genotype was determined after completion of all tests. Activity-dependent neurotrophic factor, glial fibrillary acidic protein, and vasoactive intestinal peptide expression were determined using real-time polymerase chain reaction. RESULTS:Trisomic mice achieved milestones with a significant delay in four of five motor and sensory milestones. Trisomic mice that were prenatally exposed to NAPVSIPQ+SALLRSIPA achieved developmental milestones at the same time as the controls in three of four motor and one of four sensory milestones (P<.01). Euploid pups prenatally treated with NAPVSIPQ+SALLRSIPA achieved developmental milestones significantly earlier than the euploid pups prenatally treated with placebo. Activity-dependent neurotrophic factor expression was significantly downregulated in the Ts65Dn brains compared with the controls, prenatal treatment with NAPVSIPQ+ SALLRSIPA prevented the activity-dependent neurotrophic factor decrease in the Ts65Dn brains, and the expression was not different from the controls. The glial marker glial fibrillary acidic protein demonstrated the known glial deficit in the Ts65Dn mice, and treatment with NAPVSIPQ+ SALLRSIPA prevented its downregulation. Lastly, vasoactive intestinal peptide levels were increased in the trisomic brains, whereas treatment with NAPVSIPQ+SALLRSIPA did not prevent its upregulation. CONCLUSION:Prenatal treatment with NAPVSIPQ and SALLRSIPA prevented developmental delay and the glial deficit in Down syndrome. These findings highlight a possibility for the prevention of developmental sequelae in Down syndrome and suggest a potential intervention during pregnancy that may improve the outcome.

Dataset Information

Quantitative proteomics characterization of a mouse embryonic stem cell model of Down syndrome.

Publications

Quantitative proteomics characterization of a mouse embryonic stem cell model of Down syndrome.

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