Browsing by Subject "chromosome 21"

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    Genomic Analysis of Gene Dysregulation Sites Related to Craniofacial Development in Ts65Dn Down Syndrome Mouse Embryos
    (Office of the Vice Chancellor for Research, 2015-04-17) Patel, Rushiv; Roper, Randall J.
    Down syndrome (DS) is caused by a nondisjunction event called Trisomy 21 and is known to effect every system of the body. While it is thought that select genes on chromosome 21 are responsible for specific DS phenotypes, we are unsure of the overall effect the extra genetic information poses across the genome. The presence of an extra chromosome 21 is suspected to cause dysregulation in gene expression across the genome of individuals with DS. These dysregulation sites may vary between individuals due to genetic variability and according to tissue type. Previous studies have shown that genomic regions of gene up regulation and down regulation exist in individuals with DS. Ts65Dn mice have an extra marker chromosome that accounts for approximately fifty percent of the genes that are triplicated in DS. We are using the Ts65Dn DS mouse model to study the variability in the genomic sites of dysregulation caused by trisomy and to determine whether genomic dysregulation is tissue specific. We are comparing the gene expression from genes associated with the neural tube and 1st pharyngeal arch from trisomic and euploid e9.5 embryos. This comparison may provide insight behind the effect trisomy has on genomic dysregulation that causes the small 1st pharyngeal arch and leads to a small mandible in individuals with DS. Significantly dysregulated mRNA expression levels have been collected from embryos of trisomic and euploid mice and have been characterized by next-generation sequencing. We are identifying genomic locations with the most genetic dysregulation and comparing any variability within these sites based on the spatial as well as temporal differences in mRNA expression from tissues of trisomic and euploid samples. We hypothesize that genomic gene dysregulation sites will be tissue specific. Our study aims to explain how these perturbations in gene expression may affect certain DS phenotypes such as craniofacial abnormalities.
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    MOLECULAR BASIS AND MODIFICATION OF A NEURAL CREST DEFICIT IN A DOWN SYNDROME MOUSE MODEL
    (Office of the Vice Chancellor for Research, 2012-04-13) Deitz, Samantha L.; Day, Melanie; Roper, Randall J.
    Trisomy 21 occurs in 1/700 live births and leads to phenotypes associat-ed with Down syndrome (DS), including craniofacial dysmorphology and a small mandible. Ts65Dn mice are trisomic for approximately half the genes on human chromosome 21 and display DS-like craniofacial anomalies. Cells cultured from Ts65Dn and euploid 1st pharyngeal arch (PA1) and neural tube (NT) tissues were used to analyze the effects of genetic dysregulation on cell proliferation and migration. In vitro studies revealed a proliferation deficit in trisomic PA1 and migration deficits from trisomic NT originating at embryonic day 9.5 (E9.5). DYRK1A is a gene thought to be involved in DS craniofacial development and we hypothesized that dysregulation of Dyrk1a contributes to altered craniofacial development in Ts65Dn mice. We also hypothesized that Dyrk1a agonists could be used to ameliorate this phenotype. To test our hypotheses, we quantified expression of Dyrk1a using qPCR. At E9.5, Dyrk1a is upregulated in Ts65Dn as relative to euploid PA1. We also showed that cell proliferation and migration could be returned to near euploid levels with the green tea polyphenol epigallocatechin gallate (EGCG) and harmine (known Dyrk1a inhibitors) in vitro. To further test our hypothesis, pregnant Ts65Dn and euploid mothers were treated with EGCG on E7 and E8 and E9.5 trisomic and euploid embryos were assessed for embryonic volume, PA1 vol-ume, and NCC number. Preliminary evidence suggests in vivo treatment leads to an increase in embryonic volume, PA1 volume, and NCC number in both euploid and trisomic embryos. Trisomic EGCG-treated embryos had similar PA1 volumes and NCC numbers to euploid embryos treated with PBS. Gene expression analysis of EGCG-treated NCCs is currently underway to better understand the effects of EGCG in these studies. Our results provide information about the molecular basis of DS craniofacial abnormalities and may lead to evidenced-based therapeutic options.