Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transmembrane Protein Ttyh1 Maintains the Quiescence of Neural Stem Cells Through Ca²⁺/NFATc3 Signaling.

ABSTRACT: The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6-8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.

SUBMITTER: Cao Y

PROVIDER: S-EPMC8635056 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The Hippo signalling pathway maintains quiescence in Drosophila neural stem cells.

Project description:Stem cells control their mitotic activity to decide whether to proliferate or to stay in quiescence. Drosophila neural stem cells (NSCs) are quiescent at early larval stages, when they are reactivated in response to metabolic changes. Here we report that cell-contact inhibition of growth through the canonical Hippo signalling pathway maintains NSC quiescence. Loss of the core kinases hippo or warts leads to premature nuclear localization of the transcriptional co-activator Yorkie and initiation of growth and proliferation in NSCs. Yorkie is necessary and sufficient for NSC reactivation, growth and proliferation. The Hippo pathway activity is modulated via inter-cellular transmembrane proteins Crumbs and Echinoid that are both expressed in a nutrient-dependent way in niche glial cells and NSCs. Loss of crumbs or echinoid in the niche only is sufficient to reactivate NSCs. Finally, we provide evidence that the Hippo pathway activity discriminates quiescent from non-quiescent NSCs in the Drosophila nervous system.

| S-EPMC4740179 | biostudies-literature

Foxp1 maintains hair follicle stem cell quiescence through regulation of Fgf18.

Project description:Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.

| S-EPMC3754479 | biostudies-literature

Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis.

Project description:Stem cells often divide asymmetrically to produce one stem cell and one differentiating cell, thus maintaining the stem cell pool. Although neural stem cells (NSCs) in the adult mouse subventricular zone have been suggested to divide asymmetrically, intrinsic cell fate determinants for asymmetric NSC division are largely unknown. Stem cell niches are important for stem cell maintenance, but the niche for the maintenance of adult quiescent NSCs has remained obscure. Here we show that the Notch ligand Delta-like 1 (Dll1) is required to maintain quiescent NSCs in the adult mouse subventricular zone. Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis. Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny. Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

| S-EPMC3675328 | biostudies-literature

CHD7 maintains neural stem cell quiescence and prevents premature stem cell depletion in the adult hippocampus.

Project description:Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain-helicase-DNA-binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle-aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin-remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo-insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits.

| S-EPMC5952591 | biostudies-literature

Quiescence status of glioblastoma stem-like cells involves remodelling of Ca2+ signalling and mitochondrial shape.

Project description:Quiescence is a reversible cell-cycle arrest which allows cancer stem-like cells to evade killing following therapies. Here, we show that proliferating glioblastoma stem-like cells (GSLCs) can be induced and maintained in a quiescent state by lowering the extracellular pH. Through RNAseq analysis we identified Ca2+ signalling genes differentially expressed between proliferating and quiescent GSLCs. Using the bioluminescent Ca2+ reporter EGFP-aequorin we observed that the changes in Ca2+ homeostasis occurring during the switch from proliferation to quiescence are controlled through store-operated channels (SOC) since inhibition of SOC drives proliferating GSLCs to quiescence. We showed that this switch is characterized by an increased capacity of GSLCs' mitochondria to capture Ca2+ and by a dramatic and reversible change of mitochondrial morphology from a tubular to a donut shape. Our data suggest that the remodelling of the Ca2+ homeostasis and the reshaping of mitochondria might favours quiescent GSLCs' survival and their aggressiveness in glioblastoma.

| S-EPMC6021377 | biostudies-literature

Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling.

Project description:There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell-cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.

| S-EPMC7706704 | biostudies-literature

STAT1 maintains naive CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Project description:[Figure: see text].

| S-EPMC8442933 | biostudies-literature

Dorsal-Ventral Differences in Neural Stem Cell Quiescence Are Induced by p57KIP2/Dacapo.

Project description:Quiescent neural stem cells (NSCs) in the adult brain are regenerative cells that could be activated therapeutically to repair damage. It is becoming apparent that quiescent NSCs exhibit heterogeneity in their propensity for activation and in the progeny that they generate. We discovered recently that NSCs undergo quiescence in either G0 or G2 in the Drosophila brain, challenging the notion that all quiescent stem cells are G0 arrested. We found that G2-quiescent NSCs become activated prior to G0 NSCs. Here, we show that the cyclin-dependent kinase inhibitor Dacapo (Dap; ortholog of p57KIP2) determines whether NSCs enter G0 or G2 quiescence during embryogenesis. We demonstrate that the dorsal patterning factor, Muscle segment homeobox (Msh; ortholog of MSX1/2/3) binds directly to the Dap locus and induces Dap expression in dorsal NSCs, resulting in G0 arrest, while more ventral NSCs undergo G2 quiescence. Our results reveal region-specific regulation of stem cell quiescence.

| S-EPMC6486397 | biostudies-literature

The cytosolic protein G0S2 maintains quiescence in hematopoietic stem cells.

Project description:Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G(0)/G(1) switch gene 2 (G0S2) are enriched in lineage(-) Sca-1(+) c-kit(+) (LSK) CD150(+) CD48(-) CD41(-) cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150(+) CD48(-) cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150(+) CD48(-)) and progenitor cells (LS(-)K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150(+) CD48(-) cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus.

| S-EPMC3365016 | biostudies-literature

Non-canonical Wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination.

Project description:Adult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling. Mechanistically, activation of Cdc42 induces expression of molecules involved in stem cell identity and anchorage to the niche. Strikingly, during a demyelination injury, downregulation of non-canonical Wnt-dependent Cdc42 activity is necessary to promote activation and lineage progression of quiescent NSCs, thereby initiating the process of tissue repair.

| S-EPMC5750230 | biostudies-literature