110 Oral - Neurodevelopment II/Neurobehavior II
Friday April 08, 6:00 PM - 6:15 PM

The Circular RNA Edis-Relish-Castor Axis Regulates Neurodevelopment


Authors:
Wei Liu 1; Weihong Liang 1; Xiao-Peng Xiong 2; Jian-Liang Li 3; Rui Zhou 1

Affiliations:
1) Depts. of Medicine, Biological Chemistry & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD ; Johns Hopkins All Children’s Hospital, St. Petersburg, FL ; 2) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA ; 3) NIEHS, Durham, NC

Keywords:
a. axon guidance; g. NF-kB signaling

We have identified and validated a collection of circular RNAs in Drosophila melanogaster in response to immune challenge. We show that depletion of the brain-enriched circular RNA Edis (Ect4-derived immune suppressor), but not its linear sibling Ect4, causes hyperactivation of antibacterial innate immunity signaling both in cultured cells and in vivo. Conversely, ectopic expression of Edis blocks innate immunity signaling. Our analyses reveal that Edis is enriched in neurons, and that neuron-specific depletion of Edis leads to defective axon guidance, impaired locomotive activity and shortened lifespan. Importantly, restoration of Edis expression suppresses the innate immunity hyperactivation and neurodevelopment phenotypes elicited by Edis depletion. Mechanistically, Edis encodes a functional protein that associates with and blocks the processing/activation of the innate immunity transcription factor Relish. We further show that the Castor gene, which encodes a transcription factor involved in neurodevelopment, is upregulated in Edis knockdown neurons. Notably, Castor overexpression phenocopies Edis overexpression in neurons, and reducing Caster levels suppresses the neurodevelopmental phenotypes in Edis knockdown neurons. Chromatin immunoprecipitation assay reveals that Relish associates with the promoter of Castor. In addition, we show that Relish-binding sites are required for optimal Castor promoter activity induced by either peptidoglycan treatment or Edis depletion. Lastly, Relish mutation rescues both Castor hyperactivation and neurodevelopmental phenotypes in Edis knockdown neurons. We conclude that the circular RNA Edis serves as a key modulator of innate immunity, and that the Edis-Relish-Castor axis regulates neurodevelopment.