Browsing by Subject "Craniofacial Development"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Effects of Trisomic Dyrk1a and EGCG Treatment on Craniofacial Development in Ts65Dn Down Syndrome Mice
    (Office of the Vice Chancellor for Research, 2015-04-17) Diallo, Mariyamou; Haley, Emily; Tumbleson, Danika; Roper, Randall J.
    Down syndrome (DS), also known as Trisomy 21, is a genetic disorder caused by an extra copy of human chromosome 21. Individuals with DS exhibit various phenotypes such as cognitive, skeletal and craniofacial abnormalities. The Ts65Dn mouse model displays similar craniofacial abnormalities as observed in humans with DS including a small, undersized mandible. To gain a better understanding of craniofacial abnormalities, we study the molecular and cellular mechanisms underlying these abnormalities. Previous studies conducted in our lab identified a deficit in neural crest (NC) cells in the first pharyngeal arch (PA1) or mandibular precursor by embryonic day 9.5 (E9.5). We hypothesize that the inherent molecular mechanism responsible for the small, undersized mandible is overexpression of dual-specificity tyrosine (Y) phosphorylation regulated kinase 1A (Dyrk1a), a gene that is found in three copies in individuals with DS and Ts65Dn mice. To test our hypothesis, we bred Ts65Dn mice with Dyrk1a knockout mice, thus reducing Dyrk1a copy number to normal levels. This study provides the foundation for understanding the function of Dyrk1a. We also treated embryos with Epigallocatechin gallate (EGCG), a green tea polyphenol that is known to inhibit Dyrk1a activity. We will examine the molecular and cellular effects of Dyrk1a and EGCG on the developing PA1 on E9.5 embryos. In both the genetic and pharmacological manipulations, we expect to find a larger overall embryonic size, a larger PA1 size and increased number of NC cells.
  • Thumbnail Image
    Item
    The Effects of Trisomic Dyrk1a on Ts65Dn Embryonic Craniofacial Development
    (Office of the Vice Chancellor for Research, 2015-04-17) Haley, Emily; Diallo, Mariyamou; Roper, Randall J.
    Down syndrome (DS) is caused by Trisomy 21 in humans and leads to distinctive craniofacial features in all affected individuals. The Ts65Dn mouse model of DS has orthologs of about half of the genes found on chromosome 21 and mirrors craniofacial phenotypes seen in DS including a small dysmorphic mandible. Previous studies have shown that the small mandible is due to deficits in proliferation and migration from the neural tube of neural crest cell (NCC) craniofacial precursors. Dyrk1a is a trisomic gene found in humans with DS and Ts65Dn mice, and it is overexpressed in the 1st pharyngeal arch (PA1) of our mouse model. We hypothesize that Ts65Dn, Dyrk1a+/- embryos (otherwise trisomic with the normal 2 copies of Dyrk1a) will show similar PA1 and overall embryo size as well as NCC number when compared to euploid littermates. To test our hypothesis we bred Ts65Dn, Dyrk1a+/- mothers to generate the following genotypes; Ts65Dn, Eu, Ts65Dn, Dyrk1a+/- and Eu, Dyrk1a+/-. At E9.5 embryos were removed from mothers. Using unbiased stereology on sectioned E9.5 embryos, we measured PA1 NCC number and total embryonic volume. We propose that if Ts65Dn, Dyrk1a+/- embryos show a normalized PA1, future work should be concentrated in viable therapies to target overexpression of Dyrk1a in the Ts65Dn mouse model.
  • Thumbnail Image
    Item
    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.