TREATMENT OF CRANIOFACIAL DEFICITS ASSOCIATED WITH DOWN SYN-DROME IN A MOUSE MODEL

poster abstractTrisomy 21 is the genetic source of the group of phenotypes commonly known as Down syndrome (DS). These phenotypes include cognitive im-pairment, heart defects and craniofacial abnormalities, including a small mandible. The Ts65Dn mouse model contains three copies of approximately half the genes found on human chromosome 21 and exhibits similar pheno-types to individuals with DS including a small, dysmorphic mandible. Our lab has traced this deficit to a smaller first branchial arch (BA1) consisting of fewer neural crest cells (NCCs) at embryonic day 9.5 (E9.5). At E9.5, Dyrk1a, a gene known to affect craniofacial development, is upregulated in the BA1, likely contributing to its cell deficit. Using epigallocatechin gallate (EGCG), an extract from green tea and a known inhibitor of Dyrk1a, we are attempting to rescue this deficit. We hypothesize the consumption of EGCG by pregnant mothers at E7 and E8 will rescue the mandibular deficit in de-veloping embryos by reducing the expression or activity of Dyrk1a. From our data we conclude the treatment of pregnant mothers with EGCG results in increased embryo size of trisomic embryos. Further analysis will be done to determine embryo volume, the volume of the BA1, and number of NCCs within the BA1 to determine the effects of EGCG in vivo. This research will better our understanding of craniofacial development and could lead to po-tential genetic-based therapies in the future

Mandibular and Neural Crest Cell Deficits Seen in TsDn65 Down Syndrome Mouse Model Rescued By Green Tea Polyphenol, EGCG

poster abstractDown Syndrome (DS) is caused by trisomy of the human chromosome 21 (Hsa21) and occurs in ~1 of every 700 births. DS is distinguished by over 80 phenotypic abnormalities including skeletal deficits and craniofacial phenotypes characterized by a flattened skull, slanted eyes, and a smaller mandible. To study these abnormalities, we utilize the Ts65Dn DS mouse model containing a triplication of approximately half of the gene homologues found on Hsa21 and mirrors the skeletal and mandibular phenotypes observed in DS. In Ts65Dn mice, the origin of the mandibular deficits were traced to a reduction in size of the 1st branchial arch (BA1), the developmental precursor to the mandible, occurring at embryonic day 9.5 (E9.5). At E9.5, we observe a lack of proliferation and migration of neural crest cells (NCC) from the neural tube (NT) into the BA1, causing a reduced BA1. We hypothesize that an overexpression of Dyrk1a, a Hsa21 homologue, contributes to the mandibular deficit seen in E9.5 Ts65Dn embryos. We propose that EGCG, a green tea polyphenol, will inhibit DYRK1a activity, rescuing the BA1 deficit. To test our hypothesis, Ts65Dn mothers were treated with EGCG from E0-E9.5 and sacrificed to retrieve the E9.5 embryos. Our results from unbiased stereological assessments show that E0-E9.5 EGCG in vivo treatment has the potential to increase NCC number, BA1 volume, and embryo volume of trisomic embryos. This data provide preclinical testing for a potential therapy of DS craniofacial disorders, which may extend to treating bone deficits in DS and osteoporosis

Treatment with a Green Tea Polyphenol Corrects Craniofacial Deficits Associated with Down Syndrome

poster abstractDown syndrome (DS) is caused by trisomy of human chromosome 21 (HSA21). Individuals with DS present craniofacial abnormalities including an undersized, dismorphic mandible leading to difficulty with eating, breathing, and swallowing. Using the Ts65Dn DS mouse model (three copies of ~50% HSA21 homologs), we have traced the mandibular deficit to a neural crest cell (NCC) deficiency and reduction in first pharyngeal arch (PA1 or mandibular precursor) size at embryonic day 9.5. At E9.5, Dyrk1A, a triplicated DS candidate gene, is overexpressed and may cause the NCC and PA1 deficits. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG from either E7-E8 or E0-E9.5. Our preliminary study found an increase in PA1 volume and NCC number in trisomic E9.5 embryos after treatment, but observed differences between treatment regimens. Differential gene expression was also quantified in trisomic treated embryos. This preliminary data suggests EGCG treatment has the potential to rescue the mandibular phenotype caused by trisomy. These findings provide preclinical testing for a potential therapy for craniofacial disorders linked to DS

TREATMENT OF CRANIOFACIAL DEFICITS ASSOCIATED WITH DOWN SYN-DROME IN A MOUSE MODEL

poster abstractTrisomy 21 is the genetic source of the group of phenotypes commonly known as Down syndrome (DS). These phenotypes include cognitive im-pairment, heart defects and craniofacial abnormalities, including a small mandible. The Ts65Dn mouse model contains three copies of approximately half the genes found on human chromosome 21 and exhibits similar pheno-types to individuals with DS including a small, dysmorphic mandible. Our lab has traced this deficit to a smaller first branchial arch (BA1) consisting of fewer neural crest cells (NCCs) at embryonic day 9.5 (E9.5). At E9.5, Dyrk1a, a gene known to affect craniofacial development, is upregulated in the BA1, likely contributing to its cell deficit. Using epigallocatechin gallate (EGCG), an extract from green tea and a known inhibitor of Dyrk1a, we are attempting to rescue this deficit. We hypothesize the consumption of EGCG by pregnant mothers at E7 and E8 will rescue the mandibular deficit in de-veloping embryos by reducing the expression or activity of Dyrk1a. From our data we conclude the treatment of pregnant mothers with EGCG results in increased embryo size of trisomic embryos. Further analysis will be done to determine embryo volume, the volume of the BA1, and number of NCCs within the BA1 to determine the effects of EGCG in vivo. This research will better our understanding of craniofacial development and could lead to po-tential genetic-based therapies in the future