DOWN SYNDROME AS A COMPLEX GENETIC DISORDER

Down syndrome is the most common genetic cause of intellectual disability worldwide and affects more than 400,000 adults in the United States. In the last 40 years, improvements in social supports have more than doubled the lifespan of people with Down syndrome; however, there are currently no FDA-approved treatments for Down syndrome-associated intellectual disability. As clinical trials aiming to improve the functional and adaptive skills of people with Down syndrome become a reality, the onus is on basic scientists to ensure that pre-clinical models faithfully reflect the genetic basis of trisomy 21. At the same time, improved annotation of the hundreds of gene products encoded by chromosome 21 highlights the enormous challenge of linking specific trisomic genes to specific Down syndrome phenotypes. The first two chapters of this thesis focus on animal model development and address broad issues in Down syndrome research. What makes a Down syndrome model valid? How and when should researchers compare model systems? How many trisomic genes contribute to each phenotype? Which mouse model is the “best” for pre-clinical studies? Are model systems other than mouse ever useful? The third chapter of this thesis applies these constructs to a specific Down syndrome phenotype to understand how trisomy 21 causes cerebellar hypoplasia. Previous studies showed that trisomic granule cell precursors isolated from Ts65Dn mice, the most commonly used mouse model of Down syndrome, proliferate less in response to the mitogen Sonic hedgehog than cells isolated from euploid mice. We used a series of in vitro and in vivo screens to trace this deficit in proliferation to the overexpression of multiple chromosome 21 genes. Whereas many previous studies have attempted to link a single trisomic gene to a single Down syndrome-associated phenotype, we show that many chromosome 21 genes may contribute to the dysregulation of a central signaling pathway. These results are significant because they reframe Down syndrome as a complex genetic disease and suggest that targeting a shared molecular pathway for therapeutic intervention may be more effective than targeting a single chromosome 21 gene