Haspin regulates mouse embryonic stem cell developmental potencies through Wnt5a mediated asymmetric cell division
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220824 | GEO | 2023/08/30
REPOSITORIES: GEO
Similar Datasets
Project description:Haspin regulates mouse embryonic stem cell developmental potencies through Wnt5a mediated asymmetric cell division
| PRJNA911679 | ENA
Project description:The atypical protein kinase Haspin phosphorylates Histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph creates a docking site for the Chromosomal Passenger Complex at the inner centromere, enabling correction of erratic microtubule-chromosome contacts and preventing chromosome mis-segregation. Surprisingly, Haspin knockout in the mouse does not cause developmental defects, except for testicular anomalies. Therefore, the physiological role of this kinase and the mechanistic significance of H3T3ph are in question. We show here that mouse embryonic stem cells that lack or overexpress Haspin are prone to chromosome misalignment. However, the cell population as a whole maintains the ability to expand and differentiate into multiple lineages. Although not essential for pluripotency, Haspin affects the expression of several testis-specific genes. Furthermore, the H3T3ph mark is detected in under-condensed chromatin domains of haploid spermatids, in cis with lysine/arginine methylation marks. We propose that Haspin controls a compound phospho-methyl switch and regulates testis-specific transcription.
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Project description:The strength of interactions between T cell receptors and the peptide-major histocompatibility complex (pMHC) directly modulates T cell fitness, clonal expansion, and acquisition of effector properties. Here we show that asymmetric T cell division is an important mechanistic link between increased signal strength, effector differentiation, and the ability to induce tissue pathology. Recognition of pMHC above a threshold affinity drove responding T cells into asymmetric cell division. The ensuing proximal daughters underwent extensive division and differentiated into short-lived effector cells expressing the integrin VLA-4, allowing the activated T cell to infiltrate and mediate destruction of peripheral target tissues. In contrast, T cells activated by below-threshold antigens underwent symmetric division, leading to abortive clonal expansion and failure to fully differentiate into tissue-infiltrating effector cells. Antigen affinity and asymmetric division are important factors that regulate fate specification in CD8(+) T cells and predict the potential of a self-reactive T cell to mediate tissue pathology.
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Project description:In adult Drosophila testis, asymmetric division of germline stem cells (GSCs) is specified by an oriented spindle and cortically localized adenomatous coli tumor suppressor homolog 2 (Apc2). However, the molecular mechanism underlying these events remains unclear. Here we identified Megator (Mtor), a nuclear matrix protein, which regulates GSC maintenance and asymmetric division through the spindle assembly checkpoint (SAC) complex. Loss of Mtor function results in Apc2 mis-localization, incorrect centrosome orientation, defective mitotic spindle formation, and abnormal chromosome segregation that lead to the eventual GSC loss. Expression of mitotic arrest-deficient-2 (Mad2) and monopolar spindle 1 (Mps1) of the SAC complex effectively rescued the GSC loss phenotype associated with loss of Mtor function. Collectively our results define a new role of the nuclear matrix-SAC axis in regulating stem cell maintenance and asymmetric division.
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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
Project description:NOTCH and WNT signaling pathways play critical roles in cardiac chamber formation. Here we explored the potential interactions between the two pathways in this developmental process by using genetically modified mouse models and whole embryo culture systems. By deletion of Notch1 to inactivate NOTCH1 signaling in the endocardium in vivo and ex vivo rescue experiments, we showed that myocardial WNT5A mediated endocardial NOTCH1 signaling to maintain the gene regulatory network essential for cardiac chamber formation. Furthermore, genetic deletion of β-catenin in the myocardium and inhibition of the WNT/Ca2+ signaling by FK506 resulted in a similar disruption of the gene regulatory network as inactivation of endocardial NOTCH1 signaling. Together, these findings identify WNT5A as a key myocardial factor that mediates the endocardial NOTCH signaling to maintain the gene regulatory network essential for cardiac chamber formation through WNT/β-catenin and WNT/Ca2+ signaling pathways.
| S-EPMC9531535 | biostudies-literature
Project description:Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross-omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem-like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor-initiating capacity. Meanwhile, YY2 knock-out in stem-like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin-related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic-mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.
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Project description:Asymmetric cell division of radial glial progenitors produces neurons while allowing self-renewal; however, little is known about the mechanism that generates asymmetry in daughter cell fate specification. Here, we found that mammalian partition defective protein 3 (mPar3), a key cell polarity determinant, exhibits dynamic distribution in radial glial progenitors. While it is enriched at the lateral membrane domain in the ventricular endfeet during interphase, mPar3 becomes dispersed and shows asymmetric localization as cell cycle progresses. Either removal or ectopic expression of mPar3 prevents radial glial progenitors from dividing asymmetrically yet generates different outcomes in daughter cell fate specification. Furthermore, the expression level of mPar3 affects Notch signaling, and manipulations of Notch signaling or Numb expression suppress mPar3 regulation of radial glial cell division and daughter cell fate specification. These results reveal a critical molecular pathway underlying asymmetric cell division of radial glial progenitors in the mammalian neocortex.
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Project description:Early expansion and long-term persistence predict efficacy of chimeric antigen receptor T-cells (CARTs), but mechanisms governing effector versus memory CART differentiation and whether asymmetric cell division (ACD) induces differential fates in human CARTs remain unclear. We use target-induced proximity labeling to isolate first-division proximal--daughter and distal-daughter CARTs to interrogate TCR clonality, surface proteome, and transcriptome at the single-cell level.
2024-09-27 | GSE268878 | GEO