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

• Published in: Cell stem cell Vol. 28; no. 5; pp. 967 - 977.e8
• Main Authors: bin Imtiaz, Muhammad Khadeesh, Jaeger, Baptiste N., Bottes, Sara, Machado, Raquel A.C., Vidmar, Mojca, Moore, Darcie L., Jessberger, Sebastian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.05.2021
• Subjects: Aging; Animals; asymmetric segregation; diffusion barrier; hippocampus; Hippocampus - cytology; Lamin; Lamin Type B; Mice; neural stem cell; Neural Stem Cells; Neurogenesis; nuclear lamina; Progeria; proliferation; Lamin; asymmetric segregation; neural stem cell; diffusion barrier; hippocampus; proliferation; neurogenesis; nuclear lamina; aging
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2021.01.015

Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. 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, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. 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 mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus. [Display omitted] •Lamin B1 is downregulated with age in neural stem cells (NSCs)•SUN1 protein levels increase in aged NSCs•Lamin B1 and SUN1 modulate ER membrane barrier strength•Balancing lamin B1 expression enhances neurogenesis in the aged hippocampus Advancing age impairs neural stem cell (NSC) function and causes a drop in the number of newly generated hippocampal neurons. bin Imtiaz et al. reveal a lamin-B1-mediated, cell-intrinsic mechanism that regulates hippocampal progenitor aging and show that restoring lamin B1 levels in the aged mouse hippocampus enhances stem cell proliferation and neurogenesis.