Autism spectrum disorder (ASD) is a set of conditions arising during neural development. Research into ASD has made important progress in recent years by identifying a large number of ASD risk genes. Since each of these genes accounts for a small proportion of ASD cases, it is now important to identify unifying principles that link these genes together in functionally related or coordinately regulated networks to understand the fundamental basis of ASD.
It is therefore notable that the mRNAs for a majority of high-confidence ASD risk genes bind to the translational regulatory RNA-binding protein CPEB4. Furthermore, CPEB4 expression is altered in individuals with ASD, and genetic perturbation of CPEB4 in the developing mouse cerebral cortex leads to decreased social interactions and stereotypical behaviors1. Thus, CPEB4 appears to be a key network hub for ASD risk genes. However, essentially nothing is known at the cellular mechanistic level about how this translational regulatory protein functions in cortical development.
John Flanagan and his colleagues at Harvard Medical School study neural development including the role of mRNA translational regulation2,3, and preliminary studies from his laboratory have identified a novel molecular pathway that responds to extracellular signals and regulates protein expression via the CPEB family of RNA-binding proteins. Moreover, molecules at every step of this signaling pathway have previously been implicated in ASD, and the pathway operates in cortical neurons at a key stage for ASD pathogenesis.
In the current project, Flanagan and his team plan to study this pathway by identification of target mRNAs in the cortex as well as functional studies in cultured neurons and mouse models. Findings from these studies are expected to identify principles that link together ASD risk genes and unifying cellular mechanisms, with the long-term goal of enabling future diagnostic and therapeutic approaches to ASD.