DOI
https://doi.org/10.25772/5Z08-ZZ55
Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Biology
First Advisor
Dr. Amanda J.G. Dickinson
Abstract
Down Syndrome, caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability and is associated with craniofacial anomalies. Among the triplicated genes, DYRK1A is a key contributor to the syndrome’s neurodevelopmental and craniofacial abnormalities. Recent studies suggest that DYRK1A may interact with signaling pathways, including the mTOR pathway, which regulates cell growth, proliferation, and differentiation. However, whether this is true in embryos is unknown. Using the developmental model Xenopus laevis, this study examines 1) whether inhibition of mTORC1 causes developmental differences and 2) whether Dyrk1a inhibition exacerbates differences caused by inhibition of mTOR. Exposure to Rapamycin, an mTOR inhibitor, significantly reduced body length and midface. Morphometric analysis of craniofacial shape revealed that the changes in the midface were consistent with developmental delay rather than morphological defects. Cranial cartilage analysis revealed changes in the lower jaw that were consistent with a delay in development. Time-sensitive experiments showed that the effects of rapamycin were profound during a specific period of development when specification of organs and tissues, including the face, occurs. Finally, I determined that the reduction of midface size due to rapamycin exposure was made worse when these embryos were also exposed to a Dyrk1a inhibitor. These results are the first to suggest that Dyrk1a could modulate the mTOR pathway in embryos. The preliminary experiments have been a critical step to pave the way for testing whether rapamycin could be a feasible method to correct some of the developmental alterations in animal models with excess Dyrk1a.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2025