The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton
Fernando C. Alsina,
Bianca M. Lupan,
Lydia J. Lin,
Camila M. Musso,
Federica Mosti,
Carly R. Newman,
Lisa M. Wood,
Aussie Suzuki,
Mark Agostino,
Jeffrey K. Moore,
Debra L. Silver
Affiliations
Fernando C. Alsina
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Corresponding author
Bianca M. Lupan
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Lydia J. Lin
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Camila M. Musso
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Federica Mosti
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Carly R. Newman
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
Lisa M. Wood
Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Denver, CO, USA
Aussie Suzuki
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI, USA
Mark Agostino
Curtin Health Innovation Research Institute, Curtin Medical School, and Curtin Institute for Computation, Curtin University, Bentley, WA 6102, Australia
Jeffrey K. Moore
Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Denver, CO, USA
Debra L. Silver
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences and Duke Regeneration Center, Duke University Medical Center, Durham, NC 27710, USA; Corresponding author
Summary: The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. We discover that EIF4A3 directly controls microtubules, independent of RNA, which is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract development requires only Eif4a3. Using human cortical organoids, we show that EIF4A3 disease mutations also impair neuronal growth, highlighting conserved functions relevant for neurodevelopmental pathology. Live imaging of growing neurons shows that EIF4A3 is essential for microtubule dynamics. Employing biochemistry and competition experiments, we demonstrate that EIF4A3 directly binds to microtubules, mutually exclusive of the EJC. Finally, in vitro reconstitution assays and rescue experiments demonstrate that EIF4A3 is sufficient to promote microtubule polymerization and that EIF4A3-microtubule association is a major contributor to axon growth. This reveals a fundamental mechanism by which neurons re-utilize core gene expression machinery to directly control the cytoskeleton.
