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A mechanism for the segregation of age in mammalian neural stem cells

ABSTRACT: Across life neural stem cells (NSCs) generate new neurons in the mammalian brain through asymmetric neurogenic and self-renewing cell divisions. However, the cellular mechanisms underlying NSC asymmetry remain unknown. Using fluorescence loss in photobleaching (FLIP) we here show that NSCs in vitro and within the developing forebrain generate a lateral diffusion barrier during cell division resulting in asymmetric segregation of cellular components. The strength of the diffusion barrier is dynamically regulated with age and depends on the proper function of lamin-associated nuclear envelope constituents. Strikingly, age-associated or experimental impairment of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Thus, the data presented here identify a mechanism how age is asymmetrically distributed during somatic stem cell division.

ORGANISM(S): Mus musculus

PROVIDER: GSE61367 | GEO | 2015/09/22

SECONDARY ACCESSION(S): PRJNA260886

REPOSITORIES: GEO

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A mechanism for the segregation of age in mammalian neural stem cells

Project description:Across life neural stem cells (NSCs) generate new neurons in the mammalian brain through asymmetric neurogenic and self-renewing cell divisions. However, the cellular mechanisms underlying NSC asymmetry remain unknown. Using fluorescence loss in photobleaching (FLIP) we here show that NSCs in vitro and within the developing forebrain generate a lateral diffusion barrier during cell division resulting in asymmetric segregation of cellular components. The strength of the diffusion barrier is dynamically regulated with age and depends on the proper function of lamin-associated nuclear envelope constituents. Strikingly, age-associated or experimental impairment of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Thus, the data presented here identify a mechanism how age is asymmetrically distributed during somatic stem cell division. For microarray analysis we analysed gene expression in cells derived from the hippocampi of 6 week old (young) or 9 month old (old) male C57BL/6JRj mice. 6 samples were analyzed YoungNSC, 3 replicates OldNSC, 3 replicates

2015-09-22 | E-GEOD-61367 | biostudies-arrayexpress

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

Project description: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.

2020-12-24 | GSE163795 | GEO

Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles

Project description:Aging organs functionally and structurally decline with the loss of their regenerative capabilities, yet the existence of distinct cell division programs that determine organ fates is unknown. Hair follicles, mammalian mini-organs that grow hair, miniaturize by aging. Here we report that hair follicle regeneration and aging are driven by distinct cell division types of hair follicle stem cells (HFSCs). Cell fate tracing and cell division axis analysis in mice revealed that HFSCs undergo symmetric and asymmetric cell divisions to generate a new bulge, yet preferentially provoke “stress-responsive type” asymmetric cell divisions that generate aberrantly differentiating cells upon age/stress. That dynamic program with repetitive divisions efficiently eradicates those cells through defective association and stabilization of a hemidesmosomal protein COL17A1 and a cell-polarity-protein aPKCλ in HFSCs, thereby causing organ aging. The forced stabilization of COL17A1 rescued organ aging through aPKCλ stabilization. These results demonstrate that distinct cell division programs govern tissue/organ fates.

2020-12-25 | GSE124119 | GEO

Chip-Seq of mouse Ago-1 and TRIM32-bound small RNAs from E14.5 brain.

Project description:In the mouse neocortex, neural progenitor cells generate neurons through repeated rounds of asymmetric cell division. How distinct fates are established in their daughter cells is unclear. We show here that the TRIM-NHL protein TRIM32 segregates asymmetrically during progenitor division and induces neuronal differentiation in one of the two daughter cells. TRIM32 is highly expressed in differentiating neurons. In both horizontally and vertically dividing progenitor cells, TRIM32 distribution becomes polarized in mitosis so that the protein is enriched in one of the two daughter cells. While TRIM32 overexpression induces cell cycle exit and neuronal differentiation, TRIM32 RNAi causes both daughter cells to proliferate and prevents the initiation of a neuronal differentiation program . TRIM32 ubiquitinates and degrades the transcription factor c-Myc but also binds Argonaute-1 and thereby increases the activity of specific micro-RNAs. We show that Let-7 is one of the TRIM32 targets and is required and sufficient for neuronal differentiation. Our data suggest that the asymmetric segregation of a micro RNA regulator controls self renewal in the mammalian brain. Experiment Overall Design: small RNA from total mouse brain, Ago-1 and TRIM32 IPs were cloned and sequenced using 454 GS FLX system.

2009-08-29 | E-GEOD-12633 | biostudies-arrayexpress

Islr regulates satellite cells asymmetric division through Sparc/p-ERK1/2 signaling pathway

Project description:Satellite cells are adult muscle stem cells responsible for muscle regeneration after acute or chronic injuries. The balance between stem cell self-renewal and differentiation impacts the kinetics and efficiency of skeletal muscle regeneration. This study elucidated the function of Islr in satellite cell asymmetric division. Satellite cell specific deletion of Islr compromises muscle regeneration in adult mice by impairing the satellite cell pool. Islr is pivotal for satellite cell proliferation and its deletion promotes asymmetric cell fate segregation of satellite cells. A mechanistic search revealed that Islr interacts and stabilizes the Sparc protein, which activates p-ERK1/2 signaling required for asymmetric division. In combination, the findings have identified Islr as a key regulator of satellite cell asymmetric division through the Sparc/p-ERK1/2 signaling pathway, which provides a new insight into satellite cell biology and open avenues for the treatment of myopathy.

2023-08-16 | GSE210951 | GEO

Proteasome degradative activity regulates CD8+ T lymphocyte metabolism and fate specification

Project description:Pre-effector and pre-memory cells resulting from the first CD8+ T cell division in vivo exhibit low and high rates of proteasome degradative activities, respectively. These proteasome-induced metabolic consequences were mediated in part by asymmetric segregation of Myc during cell division. Taken together, these results suggest proteasome activity as a regulator of CD8+ T lymphocyte metabolism and fate specification.

2018-02-16 | GSE78750 | GEO

Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments

Project description:Asymmetric chromosome segregation and cell division in DNA damage-induced bacterial filaments

| PRJEB40989 | ENA

Ago-1 and TRIM32-bound small RNAs from E14.5 mouse brain.

2009-03-10 | GSE12633 | GEO

A molecular framework for control of oriented cell division in the Arabidopsis embryo

Project description:Premitotic control of cell division orientation is critical for plant development, as cell walls prevent extensive cell remodelling or migration. Whilst many divisions are proliferative and add cells to existing tissues, some divisions are formative, and generate new tissue layers or growth axes. Such formative divisions are often asymmetric in nature, producing daughters with different fates. We have previously shown that in the Arabidopsis thaliana embryo, developmental asymmetry is correlated with geometric asymmetry, creating daughter cells of unequal volume. Such divisions are generated by division planes that deviate from a default “minimal surface area” rule. Inhibition of auxin response leads to reversal to this default, yet the mechanisms underlying division plane choice in the embryo have been unclear. Here we show that auxin-dependent division plane control involves alterations in cell geometry, but not in cell polarity or nuclear position. Through transcriptome profiling, we find that auxin regulates genes controlling cell wall and cytoskeleton properties. We confirm the involvement of microtubule (MT)-binding proteins in embryo division control. Topology of both MT and Actin cytoskeleton depend on auxin response, and genetically controlled MT or Actin depolymerization in embryos leads to disruption of asymmetric divisions, including reversion to the default. Our work shows how auxin-dependent control of MT- and Actin cytoskeleton properties interacts with cell geometry to generate asymmetric divisions during the earliest steps in plant development. Transcriptional profiling of Col-0 vs bdl 8-cell Arabidopsis embryos

2021-10-05 | GSE165986 | GEO

Asymmetric self-renewal associated (ASRA) genes

Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation.

2010-12-22 | GSE25334 | GEO

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