Abstract
Although adult neurogenesis recapitulates processes that occur during embryonic development, it exhibits distinct characteristics from the 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 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 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. These findings provide mechanistic insights into the differential regulation of embryonic and adult neurogenesis through developmental cytoplasmic-to-nuclear translocation of HuR.
Highlights
Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) and is required for normal brain development and function
Overexpression of focal adhesion kinase (FAK) in aNSCs phenocopies adult neurogenesis defects observed in HuR-deficient mice; inhibition of FAK activity remarkably ameliorated defective adult neurogenesis and hippocampus-dependent learning in HuR-deficient mice
HuR Regulates Neurogenesis in the Adult Brain but Not in the Embryonic Cortex To investigate the role of HuR in neurogenesis during embryonic cortical development, we generated HuR conditional knockout (HuR-cKO) mice by crossing HuRf/f mice with Emx1-Cre transgenic mice (Figure S1A)
Summary
Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) and is required for normal brain development and function. When neuroepithelial cells thicken the pseudostratified ventricular wall, they elongate and convert into radial glial cells (embryonic NSCs [eNSCs]), which generate neurons directly or indirectly via radial glial cell-derived intermediate progenitor cells (Gotz and Huttner, 2005). A subpopulation of eNSCs in the developing telencephalon begin slowly dividing and are set aside to form adult radial glia-like cells (adult NSCs [aNSCs]) in two discrete brain regions: the subventricular zone (SVZ) in the lateral ventricular wall and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus (Bond et al, 2015; Kriegstein and Alvarez-Buylla, 2009). The intrinsic molecular mechanisms underlying the differential regulation of embryonic and adult neurogenesis remain largely unknown
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