Fragile X syndrome, an autism spectrum disorder and the most common genetic form of intellectual disability in males, is caused by the loss of function of FMRP. In the current project, Gene Yeo plans to investigate whether reduction of a protein antagonist of FMRP can rescue disease-relevant deficits in human stem cell and mouse models of fragile X syndrome.

Analyzing when, how, and in which cell types autism spectrum disorder (ASD) pathology arises within the human brain will require a genetically tractable model system that can mimic human embryonic and fetal brain development. In the current project, Jürgen Knoblich’s team plans to combine 3-D tissue culture, CRISPR-based perturbations and single-cell RNA sequencing technology to study transcriptomic alterations in response to loss-of-function mutations in high-risk ASD genes. By characterizing perturbation-induced transcriptomic changes across dozens of cell types in the developing human cortex, they hope to uncover common and unique molecular pathways that bridge genetic mutations to ASD phenotypes.

Sleep disruption may be an important contributor to the core neurodevelopmental, cognitive and social challenges emblematic of autism spectrum disorders (ASDs). As a tool to discover ASD gene networks, Ravi Allada plans to perform high-throughput in vivo behavioral screening assays of transgenic RNA interference libraries in both wild-type fruit flies and flies sensitized with disruptions of ASD risk genes. Specifically, Allada’s team plans to look at altered sleep patterns and circadian rhythms. Future studies of the underlying mechanisms for these genetic pathways may lead to a better understanding of ASD pathophysiology as well as the discovery of novel therapeutic targets.