Developmental Cytoplasmic-to-Nuclear Translocation of RNA-Binding Protein HuR Is Required for Adult Neurogenesis

Although neurogenesis in the adult brain recapitulates processes that occur during embryonic development, adult neurogenesis exhibits distinct characteristics from its embryonic counterpart. However, the intrinsic mechanism underlying the differential regulation of neurogenesis between these two stages remains unclear. Herein, we show that the ablation of RNA-binding protein HuR in neural stem cells (NSCs) impairs adult, but not embryonic, neurogenesis. HuR is predominantly expressed in the cytoplasm of embryonic NSCs but translocates into the nucleus of adult NSCs. Transcriptomic analysis of HuR-deficient adult NSCs revealed that nuclear HuR primarily regulates alternative splicing of numerous premRNA transcripts, including focal adhesion kinase (FAK). HuR-deficient adult NSCs generate increased FAK mRNA isoforms with shorter 5’ UTRs, leading to enhanced FAK mRNA translation and hyperactivated FAK signaling, and inhibition of FAK ameliorates defective adult neurogenesis and impaired hippocampus-dependent learning in HuR-deficient mice. Taken together, these findings reveal novel mechanistic insights into the differential regulation of embryonic and adult neurogenesis through developmental cytoplasmic-to-nuclear translocation of HuR in NSCs.