Notch dimerization is required for leukemogenesis and T-cell development

Liu, Hudan; Anthony, Wong; Arnett, Kelly L.; Chiang, Mark Y.; Xu, Lanwei; Shestova, Olga; Wang, Hongfang; Li, Yue Ming; Bhandoola, Avinash; Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

doi:10.1101/gad.1975210

Cited by 81 publications

(106 citation statements)

References 66 publications

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“…results, N1ICD activation has been demonstrated to inhibit myeloid differentiation and to induce early stages of T-cell development from HSCs. 55 Our data additionally show that expression of N1ICD in Tie2 þ cells prevents apoptosis and disrupts the proliferation and differentiation balance of embryonic hematopoietic cell lineages. Since the equilibrium between cellular proliferation and differentiation is strictly regulated, 56 any alteration will affect lineage development.…”

Section: Discussionsupporting

confidence: 54%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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Loss-of-function studies have demonstrated the essential role of Notch in definitive embryonic mouse hematopoiesis. We report here the consequences of Notch gain-of-function in mouse embryo hematopoiesis, achieved by constitutive expression of Notch1 intracellular domain (N1ICD) in angiopoietin receptor tyrosine kinase receptor-2 (Tie2)-derived enhanced green fluorescence protein (EGFP þ ) hematovascular progenitors. At E9.5, N1ICD expression led to the absence of the dorsal aorta hematopoietic clusters and of definitive hematopoiesis. The EGFP þ transient multipotent progenitors, purified from E9.5 to 10.5 Tie2-Cre;N1ICD yolk sac (YS) cells, had strongly reduced hematopoietic potential, whereas they had increased numbers of hemogenic endothelial cells. Late erythroid cell differentiation stages and mature myeloid cells (Gr1 þ , MPO þ ) were also strongly decreased. In contrast, EGFP þ erythro-myeloid progenitors, immature and intermediate differentiation stages of YS erythroid and myeloid cell lineages, were expanded. Tie2-Cre;N1ICD YS had reduced numbers of CD41 þ þ megakaryocytes, and these produced reduced below-normal numbers of immature colonies in vitro and their terminal differentiation was blocked. Cells from Tie2-Cre;N1ICD YS had a higher proliferation rate and lower apoptosis than wild-type (WT) YS cells. Quantitative gene expression analysis of FACS-purified EGFP þ YS progenitors revealed upregulation of Notch1-related genes and alterations in genes involved in hematopoietic differentiation. These results represent the first in vivo evidence of a role for Notch signaling in YS transient definitive hematopoiesis. Our results show that constitutive Notch1 activation in Tie2 þ cells hampers YS hematopoiesis of E9.5 embryos and demonstrate that Notch signaling regulates this process by balancing the proliferation and differentiation dynamics of lineage-restricted intermediate progenitors.

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Section: Discussionsupporting

confidence: 54%

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

et al. 2014

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“…on April 30, 2019. by guest www.bloodjournal.org From were expressed at similar levels in both groups, indicating that Wnt4 did not enhance general Notch activation. 36 In contrast, the expression of Ptcra and the polarity complex gene Scrib was decreased in the presence of Wnt4. Scribble inhibition in fetal liver progenitor cells results in a partial block during DN3 progression.…”

Section: Wnt4 In Fetal and Postnatal Thymopoiesis 5167mentioning

confidence: 88%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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“…qPCR was conducted using FAST SYBR Green Master Mix (Bio-Rad) on CFX Connect Real-Time PCR System (Bio-Rad). Relative expression of the mRNA was estimated using the 2 ÀDDCt method (21). Primer sequences for real-time PCR were listed in Supplementary Table S2.…”

Section: Rna Extraction and Qrt-pcrmentioning

confidence: 99%

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

et al. 2015

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a high rate of metastasis. Numerous signaling events have been implicated in the molecular pathogenesis of this neoplasm. Aberrantly high expression of JAGGED2, one of the NOTCH ligands, often occurs in human PDAC. However, what role JAGGED2 plays in the disease development and whether JAGGED2 executes its function through activating NOTCH signaling remain to be determined. We report here that JAGGED2 plays a critical role in promoting PDAC metastasis in vitro and in vivo. Depletion of JAGGED2, but not its homolog JAGGED1, profoundly inhibited both migration and invasion without influencing cell proliferation. Furthermore, reconstitution of JAGGED2 expression rescued the migratory defect. Surprisingly, neither pharmacologic nor genetic inhibition of NOTCH downstream signaling resulted in obvious defect in metastasis. Instead, depletion of NOTCH1 expression per se gave rise to migratory defects similar to JAGGED2 ablation. Moreover, blockade of ligand-receptor interaction by a specific JAGGED2-Fc fusion protein dramatically inhibited PDAC cell migration, suggesting that tumor metastasis relies on physical interactions of JAGGED2-NOTCH1 but not Notch downstream signaling activation. Taken together, our data reveal a novel role of NOTCH in regulation of PDAC metastasis, and identify JAGGED2 as a critical mediator in this event. These findings also provide rationale for developing small molecules or biologic agents targeting JAGGED2 for therapeutic intervention.

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Notch dimerization is required for leukemogenesis and T-cell development

Cited by 81 publications

References 66 publications

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Notch1 regulates progenitor cell proliferation and differentiation during mouse yolk sac hematopoiesis

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

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