Highlights d CELF2 variants disrupt nucleocytoplasmic localization and human cortical development d Nuclear translocation of CELF2 marks neural stem cells that undergo differentiation d Cytoplasmic CELF2 regulates mRNA encoding cell fate and disease-related factors d Cytoplasmic CELF2 regulates fate decisions of neural stem cells

No abstract

The formation of the cerebral cortex requires balanced expansion and differentiation of neural progenitor cells, the fate choice of which requires regulation at many steps of gene expression. As progenitor cells often exhibit transcriptomic stochasticity, the ultimate output of cell fate-determining genes must be carefully controlled at the post-transcriptional level, but how this is orchestrated is poorly understood. Here we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb neural progenitor cell fate decisions in mice by disrupting the nucleocytoplasmic transport of CELF2. In self-renewing neural progenitors, CELF2 is localized in the cytoplasm where it binds and coordinates mRNAs that encode cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNAs for translation and thereby triggers neural progenitor differentiation. Our results reveal a mechanism by which transport of CELF2 between discrete subcellular compartments orchestrates an RNA regulon to instruct cell fates in cerebral cortical development.