Bigham, Caymee, Syed, Briana, Smith, Sofia, Nordquist, Sarah, Pierce, Jon, Perks, Katherine, Sanchez, Sophia
[
International Worm Meeting,
2021]
Down syndrome (DS) is caused by overexpression of 21st chromosome (Hsa21) genes due to the presence of an extra copy of Hsa21. A major goal in DS research is to understand the individual contribution of each Hsa21 gene to the numerous phenotypes that accompany DS. Progress is being made using mouse models to understand the role of certain Hsa21 genes. However, most Hsa21 genes have not been studied in any detail. To circumvent the time and cost of mouse models for single-gene studies, we are leveraging the speed and affordability of the nematode C. elegans. Our lab found that C. elegans has 51 highly-conserved orthologs of Hsa21 genes. By studying loss-of-function mutants and performing RNAi for these orthologs, we found that 14 are essential and 10 are required for neural or muscular function in C. elegans -- 3 of which had not previously been studied. Through epistasis analysis, we found that the novel molecule, MTQ-2, appears to modify G-protein signaling to regulate rates of cholinergic synaptic transmission. Additionally, to probe how overexpression (OE) of individual Hsa21 genes contributes to neuronal, muscular, and developmental phenotypes related to DS, we are generating a complementary set of 51 C. elegans transgenic strains that each overexpress a different Hsa21 ortholog. We are performing quantitative behavioral analyses with the OE strains to deduce which genes cause neural or muscular dysfunction when overexpressed. Thus far, we discovered a specific behavioral defect for six OE strains including EVA-1, a novel slit receptor involved in axon guidance recently discovered in C. elegans. By identifying Hsa21 genes that cause phenotypes when overexpressed in C. elegans, this study will highlight individual Hsa21 genes and pathways to prioritize for further study in other models and to consider as potential therapeutic targets for improving health in those with DS.