Proteomic Identification of Protein Misexpression During Cardiogenesis in the Ts65Dn Down Syndrome Mouse Model
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Down syndrome (DS), a complex genetic disorder in humans, is due to the triplication of human chromosome 21 and results in congenital heart defects in approximately 50% of DS newborns. The Ts65Dn mouse model has various phenotypes corresponding to those found in human DS, including neonatal lethality and cardiovascular defects. We expect that dosage imbalance in Ts65Dn embryos causes misexpression of triplicated genes, thereby disrupting expression of other genes throughout the genome and the resulting protein products of those genes, which then produces the observed cardiovascular abnormalities. We utilized proteomics to examine the array of proteins expressed at embryonic day E14.5 and E13.5, during the final stages of cardiac septation. At E13.5, ten proteins with varied expression between euploid and trisomic samples were identified, and nine proteins were identified at E14.5. Ezrin, one of the proteins identified as overexpressed at E14.5 in trisomic hearts, is located on centromeric Mmu17, which is triplicated in the Ts65Dn mouse model. The 1.5 fold level of Ezrin protein, verified with immunoblotting, provides “proof of principle” that proteomic analysis of small embryonic tissues is a viable method for detecting and identifying protein misexpression during trisomic development. Mlc2a, overexpressed at E14.5, and Mlc2v, underexpressed at E14.5, are two proteins critical during septation of the heart and chamber specification. Preliminary work with verification using immunoblotting and immohistochemistry, suggests a possible misexpression. This work represents a novel approach to evaluating the effects of dosage imbalance during trisomic development and has identified multiple proteins whose abnormal expression may disrupt the normal protein milieu during cardiogenesis producing the pathological conditions seen in trisomic embryos with cardiovascular defects.
Franklin and Marshall College Archives, Undergraduate Honors Thesis 2012
- F&M Theses Collection 
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