Identification of Notch ligand useage by splenic B cells using Dll1 and Dll4 Notch ligand blockade.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274991 | GEO | 2024/10/18
REPOSITORIES: GEO
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Project description:Marginal zone (MZ) B cells leverage Notch2 signals to attain rapid differentiation responses and positional cues with in the spenic environment. While it is known that a major player in Notch2 signaling in MZ B cells is the proto-oncogene Myc, it is not clear to what extent MZ B cells use Notch2 signals in Myc-independent manner. In this study we conditinally and inducibly deleted Myc in mature B cells and then used in vivo delivery of anti-Notch2 antibodies to separated Myc-dependent and -independent Notch2 signaling in MZ B cells.
2024-10-18 | GSE274989 | GEO
Project description:Identification of Notch ligand useage by splenic B cells using Dll1 and Dll4 Notch ligand blockade.
| PRJNA1148919 | ENA
Project description:Marginal zone (MZ) B cells have innate-like response characteristics due to a unique ability receive and integrate Notch2 signals in the spleen. There is evidence showing MZ B cells receive these signals both in the marginal sinus and the B cell follicle. The relative strength and conservation of these Notch signals is not yet clear. Therefore, we generated mice in which S1pr1 is deleted in mature B cells. These mice have MZ B cells by phenotype but these cells are retained in the follicle and unable to transit to the marginal zone. In this experiment we examined the impact of Notch2 signaling in these cells and cre expressing control animals using in vivo anti-Notch2 antibody blockade followed by RNA-sequencing.
2024-10-18 | GSE274990 | GEO
Project description:Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool). In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity) raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt) and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki), we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM) where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4.
| S-EPMC4482573 | biostudies-literature
Project description:Background & aimsAblation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4).MethodsTransgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ER(T2)).ResultsNotch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4(+), Lgr5(+), and Ascl2(+)). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut.ConclusionsNotch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice.
| S-EPMC3066401 | biostudies-literature
Project description:(1) Assessment of the transcriptional changes regulated by KLHL6 upon NOTCH ligand stimulation. Bulk RNA-seq in KLHL6 WT or KO U2932 cells was performed upon incubation with stromal OP9 cells stably expressing NOTCH ligand DLL1. (2) Assessment of the transcriptional changes regulated by the KLHL6-NOTCH2 axis in a xenotransplant model of DLBCL. Bulk RNA-seq was performed in in KLHL6+/+NOTCH2+/+(WT), KLHL6-/-NOTCH2+/+(K6-KO), KLHL6+/+NOTCH2-/-(N2-KO), KLHL6-/-NOTCH2-/-(DKO) U2932 cells xenotranplanted in NSG mice trated with CHOP. (3) Assessment of the transcriptional changes regulated by the DLBCL-associated NOTCH2 mutants. Bulk RNA-seq was performed inU2932 cells stably expressing NOTCH2(WT), NOTCH2(S2156A), NOTCH2(R2400*) or NOTCH2(Q2140*).
2024-05-03 | GSE231624 | GEO
Project description:Reports have suggested that the two Notch ligands, Dll1 and Dll4, are indispensable to maintain the homeostasis of the intestinal epithelium. However, within the intestinal epithelium, the precise distribution of the cells that express those ligands at the protein level remains largely unknown. Here, we show a series of immunohistochemical analysis through which we successfully identified mice intestinal epithelial cells (IECs) that endogenously express Dll1 or Dll4. Results showed that Dll1-positive (Dll1+ve) IECs reside exclusively within the crypt, whereas Dll4-positive (Dll4+ve) IECs can locate both in the crypt and in the villus of the small intestine. Also in the colon, Dll1+ve IECs resided at the lower part of the crypt, whereas Dll4+ve IECs resided at both upper and lower part of the crypt, including the surface epithelium. Both Dll1+ve and Dll4+ve IECs were ATOH1-positive, but Hes1-negative cells, and located adjacent to Hes1-positive cells within the crypts. A sub-population of both Dll1+ve and Dll4+ve IECs appeared to co-express Muc2, but rarely co-expressed other secretory lineage markers. However, as compared to Dll1+ve IECs, Dll4+ve IECs included larger number of Muc2-postive IECs, suggesting that Dll4 is more preferentially expressed by goblet cells. Also, we identified that Dll4 is expressed in the Paneth cells of the small intestine, whereas Dll1 and Dll4 is expressed in the c-kit-positive IECs of the colon, indicating that Dll1+ve and Dll4+ve IECs may contribute to constitute the intestinal stem cell niche. Compared to the normal colon, analysis of DSS-colitis showed that number of Dll1+ve IECs significantly decrease in the elongated crypts of the inflamed colonic mucosa. In sharp contrast, number of Dll4+ve IECs showed a significant increase in those crypts, which was accompanied by the increase in number of Hes1-positive IECs. Those Dll4+ve IECs were mostly found adjacent to the Hes1-positive IECs, suggesting that Dll4 may act as a major Notch ligand in the crypts of the inflamed colonic mucosa. Our results illustrate distinct expression patterns of Dll1 and Dll4 within the intestinal epithelium, and suggest that these two ligands may have different roles in normal and inflamed mucosa.
| S-EPMC4017886 | biostudies-literature
Project description:The lactate receptor GPR81 contributes to cancer development, yet the mechanisms remain unclear. Here, we show that GPR81 is upregulated in human cancers and further upregulated by extracellular lactate and three-dimensional growth of breast cancer spheroids. GPR81 knockdown (KD) increased spheroid necrosis and reduced invasion and in vivo tumor growth. GPR81 KD altered GO terms relating to extracellular matrix (ECM) and cell adhesion, including upregulation of Protocadherin-7 (PCDH7), which exhibited a striking, clustered expression in spheroids. Single cell analysis revealed that PCDH7 was inversely related with Ki-67 and co-clustered with other GPR81 KD-upregulated genes including Ephrin-type-A receptor-7 (EPHA7). The matricellular protein SPARC and the Notch ligand Delta-like-4 (DLL4), were downregulated upon GPR81 KD, and their KD elicited spheroid necrosis (DLL4) and inhibited invasion. We conclude that GPR81 supports breast cancer aggressiveness at least in part via SPARC and DLL4. Our findings substantiate GPR81 as a promising target in breast cancer treatment.
2022-05-23 | GSE203441 | GEO
Project description:Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.
| S-EPMC6731356 | biostudies-literature
Project description:We report the cloning and characterization of a new member of the Delta family of Notch ligands, which we have named Dll4. Like other Delta genes, Dll4 is predicted to encode a membrane-bound ligand, characterized by an extracellular region containing several EGF-like domains and a DSL domain required for receptor binding. In situ analysis reveals a highly selective expression pattern of Dll4 within the vascular endothelium. The activity and expression of Dll4 and the known actions of other members of this family suggest a role for Dll4 in the control of endothelial cell biology.
| S-EPMC316657 | biostudies-literature