Declining Lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity

Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus (DG). With advancing age levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here we show that the nuclear lamina protein Lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs. LB1 is cross-regulated with Sun-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), a disease of premature aging. LB1 and SUN1 govern the strength of a diffusion barrier in the membrane of the endoplasmic reticulum (ER) that is associated with the segregation of aging factors during NSC divisions. Balancing the levels of LB1 and SUN1 in aged NSCs restores the ER-diffusion barrier. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a novel mechanism associated with the age-related decline of neurogenesis in the mammalian hippocampus. Overall design: Comparison between young vs old NSCs and between old NSCs retrovirally transduced with IRES-CFP or Lamin B1-over-expressing-IRES-CFP. 100 cells of each condition were flow sorted into one well of a 384-well plate containing lysis buffer. 4 biological replicates were generated per condition (16 samples total). Wells in the 384-well were processed according to the SmartSeq2 protocol using a microliter pipetting robot and sequenced on an Illumunia NovaSeq.