Mutations in the exon junction complex (EJC) components can cause neurodevelopmental disorders, demonstrating a vital role for EJC-mediated RNA metabolism in brain development. Here, Debra Silver and colleagues uncover a key role for EIF4A3, a core EJC protein, in mediating neurogenesis in mouse and human neural progenitors. First, the authors observe extensive cell death and impaired brain development in Eif4a3 haploinsufficient mutant mice. Using live imaging, they find that mitosis of the progenitors in these mice is delayed, leading to more neuronal progeny and cell death. Previous studies have also observed links between mitosis duration and altered progenitor fate. To disentangle effects on cell fate and cell death, the authors look at Eif4a3;p53 compound mutant mice, and find that although most brain defects can be rescued by preventing p53-dependent apoptosis, there are additional p53-independent mechanisms through which EIF4A3 contributes to neurogenesis. Importantly, the authors observe that these progenitor defects are recapitulated in human pluripotent stem cell-derived organoids where EIF4A3 is mutated. Finally, the authors present evidence showing that EIF4A3 acts together with other EJC components to control progenitor function. Overall, this study provides new insights into the mechanisms of brain development, identifying a conserved role of EIF4A3 in mitosis, cell fate and the regulation of neural progenitors.
