The exon junction complex component EIF4A3 is essential for mouse and human cortical progenitor mitosis and neurogenesis

Abstract

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.

Entosis implicates a new role for P53 in microcephaly pathogenesis, beyond apoptosis

“…Eif4a3 [36,49] Microcephaly in mice, neurodevelopmental defects in human Mitotic delay and cortical organization defects Yes Untested Partial rescue RBM8A [36] Microcephaly in mice, neurodevelopmental defects in human Mitotic delay and cortical organization defects…”

“…[29,42] In a recent study of the Eif4a3 mutant, P53 elimination partly rescued cell death and restored deep cortical layers, but not upper layers, suggesting that Eif4a3-associated microcephaly occurs due to both P53-dependent and -independent mechanisms. [36,49] Since this study did not examine activation or activity of MSP components, such as P53BP or USP28, it is uncertain whether MSP mediates P53 activation in EJC mutant models (Figure 2).…”