PROJECT SUMMARY
There are no approved drug therapies to prevent or reverse intellectual disability in neurodevelopmental
disorders. Down syndrome (DS) is the most prevalent genetic cause of intellectual disability, yet it is exceedingly
complex to understand and treat as hundreds of genes on the triplicated human chromosome 21 (Hsa21) may
contribute to its presentation. New approaches are needed to dissect these many genetic influences and their
potential interactions on the development of the body and brain. The larval zebrafish offers a solution to this
large-scale challenge, as many genes can be manipulated and resulting phenotypes compared with highly
sensitive methods. Relevant features of this animal model include optical transparency, external development,
genetic conservation, and a vertebrate nervous system structure. The similarity of zebrafish and human proteins
and signaling pathways supports their use in high-throughput drug discovery, and multiple compounds identified
in zebrafish studies have entered clinical trials. With this study, we will address the need for new treatments for
intellectual disability in DS by investigating disrupted mechanisms of brain development and by screening for
small molecules that can prevent observed abnormalities. For Aim 1 of this proposal, we will define the effect of
overexpressing many Hsa21 genes individually and in combination on zebrafish development, brain activity,
brain structure, and behavior. This aim follows a pipeline we previously used successfully for a large screen of
genes associated with schizophrenia. While Aim 1 will cast a wide net, agnostic to which signaling pathways
might be affected, Aim 2 will directly investigate a defective cellular response to the Sonic hedgehog mitogen
that has been strongly implicated by mouse studies and DS phenotypes. Using classical developmental biology
approaches and cutting-edge genomics, we will study a particular factor highlighted by recent cell culture studies.
We hypothesize that increased levels of this Hsa21 gene reshapes the epigenome during early embryonic
development to cause a reduced response to Hedgehog signaling. Building on phenotypes for this promising
candidate, we will screen for other Hsa21 genes that impart synergistic or opposing effects on Hedgehog
responsiveness. Defining how Hsa21 genes contribute to signaling deficits will clarify the underlying processes
disrupted in DS, yield fundamental knowledge of neural development, highlight novel protein targets for drug
discovery, and establish phenotypes to rescue in future drug screens. Finally, for Aim 3, we will screen for small
molecules that can prevent developmental phenotypes in zebrafish. Taken together, the proposed aims will
provide a foundation for understanding the causes of DS and set the stage for multiple translational efforts.
