The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton

Summary The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. Unexpectedly, we discover that EIF4A3 directly controls microtubules independent of RNA, and this is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract formation requires only Eif4a3 . Using human cortical organoids, we demonstrate that EIF4A3 disease mutations also impair neuronal maturation, highlighting conserved functions relevant for neurodevelopmental pathology. Employing biochemistry and molecular modeling we discover that EIF4A3 directly binds to microtubules, mutually exclusive of the RNA-binding complex. In growing neurons, EIF4A3 is essential for microtubule dynamics, and sufficient to promote microtubule polymerization and stability in vitro . Together, our data show that tubulin-bound EIF4A3 orchestrates microtubule dynamics, underlying key events of neuronal development. This reveals a new mechanism by which neurons re-utilize core gene expression machinery to rapidly and directly control the cytoskeleton. Highlights The Exon Junction Complex controls neuronal survival but only EIF4A3 directs axonal growth EIF4A3 controls axonal tract formation in vivo. Human EIF4A3 deficient iPSC-derived cortical organoids recapitulate neuronal defects. EIF4A3 directly binds to microtubules to control their growth and stability in neurons.