Similar Datasets
Project description:Notch1 signaling ramps up to very high levels in order to drive CD4-CD8- double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. During this important phase of T-cell development, which is known as the DN-DP transition, it is unclear whether the Notch1 complex simply strengthens its signal output as an isolated unit or recruits cofactors to amplify its signals. We previously showed that the PIAS-like coactivator Zmiz1 is a direct and context-dependent cofactor of Notch1 in T-cell leukemia. Using conditional knockout mouse models, we show that like inactivation of Notch, inactivation of Zmiz1 impaired the DN-DP transition under steady state and stress conditions. To determine mechanism, we performed RNA-Seq on sorted DN3 cells that were deprived of Zmiz1 signals either acutely (DeltaTamCre) or chronically (DeltaMxCre). To differentiate Notch1-independent from Notch1-dependent target genes, we also performed RNA-Seq on DN3 cells that were deprived of Notch1 signals using the anti-NRR Notch1 antibody. Our data suggests that Zmiz1 selectively amplifies a subset of Notch1 target genes in DN3 cells, such as Myc.
2018-09-21 | GSE106683 | GEO
Project description:Notch1 signaling ramps up to very high levels in order to drive CD4-CD8- double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. During this important phase of T-cell development, which is known as the DN-DP transition, it is unclear whether the Notch1 complex simply strengthens its signal output as an isolated unit or recruits cofactors to amplify its signals. We previously showed that the PIAS-like coactivator Zmiz1 is a direct and context-dependent cofactor of Notch1 in T-cell leukemia. Using conditional knockout mouse models, we show that like inactivation of Notch, inactivation of Zmiz1 impaired the DN-DP transition under steady state and stress conditions. To determine mechanism, we performed RNA-Seq on sorted early T-lineage progenitor (ETP) and DN3 cells that were deprived of Zmiz1 signals either acutely (DeltaTamCre) or chronically (DeltaMxCre). To differentiate Notch1-independent from Notch1-dependent target genes, we also performed RNA-Seq on ETP and DN3 cells that were deprived of Notch1 signals using the anti-NRR Notch1 antibody. Our data suggests that Zmiz1 selectively amplifies a subset of Notch1 target genes in DN3 cells, such as Myc. In contrast, Zmiz1 does not have these functions in ETP cells, thus indicating stage-specific roles of Zmiz1.
2018-09-21 | GSE116120 | GEO
Project description:The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis
| PRJNA477341 | ENA
Project description:The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [DN3]
| PRJNA417671 | ENA
Project description:The Zmiz1-Notch1 interaction induces Myc expression to drive steady state and stress thymopoiesis [ETP and DN3]
| PRJNA477331 | ENA
Project description:Activating NOTCH1 mutations are found in 50% to 60% of human T-cell acute lymphoblastic leukemia (T-ALL) samples. In mouse models, these mutations generally fail to induce leukemia. This observation suggests that NOTCH1 activation must collaborate with other genetic events. Mutagenesis screens previously implicated ZMIZ1 as a possible NOTCH1 collaborator in leukemia. ZMIZ1 is a transcriptional coactivator of the protein inhibitor of activated STAT (PIAS)-like family. Its role in oncogenesis is unknown. Here, we show that activated NOTCH1 and ZMIZ1 collaborate to induce T-ALL in mice. ZMIZ1 and activated NOTCH1 are coexpressed in a subset of human T-ALL patients and cell lines. ZMIZ1 inhibition slowed growth and sensitized leukemic cells to corticosteroids and NOTCH inhibitors. Gene expression profiling identified C-MYC, but not other NOTCH-regulated genes, as an essential downstream target of ZMIZ1. ZMIZ1 functionally interacts with NOTCH1 to promote C-MYC transcription and activity. The mechanism does not involve the NOTCH pathway and appears to be indirect and mediated independently of canonical PIAS functions through a novel N-terminal domain. Our study shows the importance of identifying genetic collaborations between parallel leukemic pathways that may be therapeutically targeted. They also raise new inquiries into potential NOTCH-ZMIZ1 collaboration in a variety of C-MYC-driven cancers.
| S-EPMC3549029 | biostudies-literature
Project description:Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele because insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are coexpressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out nonoverlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages.
| S-EPMC3167359 | biostudies-literature
Project description:MODFLOW is one of the most popular groundwater simulation tools available; however, the development of lake modules that can be coupled with MODFLOW is lacking apart from the LAK3 package. This study proposes a new approach for simulating lake-groundwater interaction under steady-state flow, referred to as the sloping lakebed method (SLM). In this new approach, discretization of the lakebed in the vertical direction is independent of the spatial discretization of the aquifer system, which can potentially solve the problem that the lake and groundwater are usually simulated at different scales. The lakebed is generalized by a slant at the bottom of each lake grid cell, which can be classified as fully submerged, dry, and partly submerged. The SLM method accounts for all lake sources and sinks, establishing a governing equation that can be solved using Newton's method. A benchmarking case study was conducted using a modified model setup in the LAK3 user manual. It was found that when there is a sufficient number of layers at the top of the groundwater model, SLM simulates an almost identical groundwater head as the LAK3-based model; when the number of layers decreases, SLM is unaffected while LAK3 may be at a risk of giving unrealistic results. Additionally, the SLM can reflect the relationship between the simulated lake surface area and lake water depth more accurately. Therefore, the SLM method is a promising alternative to the LAK3 package when simulating lake-groundwater interaction.
| S-EPMC7891635 | biostudies-literature
Project description:The skin hosts a variety of dendritic cells (DCs), which act as professional APC to control cutaneous immunity. Langerhans cells (LCs) are the only DC subset in the healthy epidermis. However, due to the complexity of the skin DC network, their relative contribution to either immune activation or immune tolerance is still not entirely understood. To specifically study the function of LCs in vivo, without altering the DC subset composition in the skin, we have generated transgenic mouse models for tamoxifen-inducible de novo expression of Ags in LCs but no other langerin+ DCs. Therefore, this system allows for LC-restricted Ag presentation to T cells. Presentation of nonsecreted OVA (GFPOVA) by steady-state LCs resulted in transient activation of endogenous CTL in transgenic mice. However, when these mice were challenged with OVA by gene gun immunization in the contraction phase of the primary CTL response they did not respond with a recall of CTL memory but, instead, with robust Ag-specific CTL tolerance. We found regulatory T cells (Tregs) enriched in the skin of tolerized mice, and depletion of Tregs or adoptive experiments revealed that Tregs were critically involved in CTL tolerance. By contrast, when OVA was presented by activated LCs, a recallable CTL memory response developed in transgenic mice. Thus, neoantigen presentation by epidermal LCs results in either robust CTL tolerance or CTL memory, and this decision-making depends on the activation state of the presenting LCs.
| S-EPMC5563165 | biostudies-literature
Project description:During steady-state walking, mediolateral gait stability can be maintained by controlling the center of pressure (CoP). The CoP modulates the moment of the ground reaction force, which brakes and reverses movement of the center of mass (CoM) towards the lateral border of the base of support. In addition to foot placement, ankle moments serve to control the CoP. We hypothesized that, during steady-state walking, single stance ankle moments establish a CoP shift to correct for errors in foot placement. We expected ankle muscle activity to be associated with this complementary CoP shift. During treadmill walking, full-body kinematics, ground reaction forces and electromyography were recorded in thirty healthy participants. We found a negative relationship between preceding foot placement error and CoP displacement during single stance; steps that were too medial were compensated for by a lateral CoP shift and vice versa, steps that were too lateral were compensated for by a medial CoP shift. Peroneus longus, soleus and tibialis anterior activity correlated with these CoP shifts. As such, we identified an (active) ankle strategy during steady-state walking. As expected, absolute explained CoP variance by foot placement error decreased when walking with shoes constraining ankle moments. Yet, contrary to our expectations that ankle moment control would compensate for constrained foot placement, the absolute explained CoP variance by foot placement error did not increase when foot placement was constrained. We argue that this lack of compensation reflects the interdependent nature of ankle moment and foot placement control. We suggest that single stance ankle moments do not only compensate for preceding foot placement errors, but also assist control of the subsequent foot placement. Foot placement and ankle moment control are 'caught' in a circular relationship, in which constraints imposed on one will also influence the other.
| S-EPMC8563802 | biostudies-literature