The Exon-junction Complex Component EIF4A3 is Essential for Mouse and Human Cortical Progenitor Mitosis and Neurogenesis

Mutations in components of the exon junction complex (EJC) are associated with neurodevelopment and disease. In particular, reduced levels of the RNA helicase EIF4A3 cause Richieri-Costa-Pereira Syndrome (RCPS) and CNVs are linked to intellectual disability. Consistent with this, Eif4a3 haploinsufficient mice are microcephalic. Altogether, this implicates EIF4A3 in cortical development; however, the underlying mechanisms are poorly understood. Here, we use mouse and human models to demonstrate that EIF4A3 promotes cortical development by controlling progenitor mitosis, cell fate, and survival. Eif4a3 haploinsufficiency in mice causes extensive cell death and impairs neurogenesis. Using Eif4a3;p53 compound mice, we show that apoptosis is most impactful for early neurogenesis, while additional p53-independent mechanisms contribute to later stages. Live imaging of mouse and human neural progenitors reveals Eif4a3 controls mitosis length, which influences progeny fate and viability. These phenotypes are conserved as cortical organoids derived from RCPS iPSCs exhibit aberrant neurogenesis. Finally, using rescue experiments we show that EIF4A3 controls neuron generation via the EJC. Altogether, our study demonstrates that EIF4A3 mediates neurogenesis by controlling mitosis duration and cell survival, implicating new mechanisms underlying EJC-mediated disorders.Next, we focus on the function of EIF4A3 in neurons. We unexpectedly discovered that that Eif4a3 – but not Magoh or Rbm8a – is required for neuronal maturation and development of the axonal tract using genetic mouse models. Here we use neuronal cultures, super resolution imaging, and biochemical assays and show that EIF4A3 controls neurite outgrowth in an EJC-independent manner and binds directly to microtubules. Additionally, we perform quantitative proteomics to ask whether other interactors of EIF4A3 vary across progenitors and neurons in the developing brain, finding an enrichment of cell cycle regulators during early neurogenesis and cytoskeletal regulators in later neurogenesis. Altogether, these data argue that EIF4A3 has cell-type specific functions and controls brain development through multiple mechanisms.