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PubMed2005

Fringe-dependent notch activation and tramtrack function are required for specification of the polar cells in Drosophila oogenesis.

During Drosophila oogenesis, each egg chamber is encapsulated through the coordinated signaling of multiple pathways, resulting in the formation of polar cells at the termini and a row of stalk cells in between each egg chamber. Notch signaling is required for specification of a precursor group containing both stalk and polar cells. Together, the Notch and JAK/STAT pathways specify the stalk cells as well as a group of prepolar cells, from within that group. The mechanism by which the polar cells differentiate from the prepolar group involves apoptosis, but the pathways which control that process are largely unknown. We now demonstrate that Notch signaling, activated by Delta and transduced by the transcription factor Tramtrack, is involved in the process of refining the prepolar cell group to two polar cells. The glycosyltransferase Fringe is expressed and required cell-autonomously in prepolar cells for this process. However, the transcription factor Mirror, which inhibits fringe expression in other tissues and stages of development, as well as Serrate, one of the two known ligands for Notch, are not required for maturation of prepolar cells. This finding suggests that Fringe is necessary for generating positional information in localizing a high-affinity interaction between Notch and its ligand Delta, even if a second ligand is not essential.

Animals↗
PubMed1996

Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.

Amino Acid Sequence↗
PubMed2006

E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment.

The helix-loop-helix protein, E47, is essential for both B- and T-lineage development. Here we demonstrate that in vitro E47 and Notch signaling act in concert to promote T cell development from fetal hematopoietic progenitors and to restrain development into the natural killer and myeloid cell lineages. The expression of an ensemble of genes associated with Notch signaling is activated by E47, and additionally, Notch signaling and E47 act in parallel pathways to induce a T lineage-specific program of gene expression. Enforced expression of the intracellular domain of Notch rescues the developmental arrest at the T cell commitment stage in E2A-deficient fetal thymocytes. Finally, we demonstrate that regulation of Hes1 expression by Notch signaling and E47 is strikingly similar to that observed during Drosophila melanogaster sensory development. Based on these observations, we propose that in developing fetal thymocytes E47 acts to induce the expression of an ensemble of genes involved in Notch signaling, and that subsequently E47 acts in parallel with Notch signaling to promote T-lineage maturation.

Animals↗
PubMed2006

Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia.

Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells overexpress pTalpha/pre-TCR and display constitutive activation of NF-kappaB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kappaB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-kappaB via IKKbeta/IKKalpha/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-alpha genes. In contrast, upon pTalpha deletion, Notch3 binds IKKalpha and maintains NF-kappaB activation through an alternative pathway, depending on an NIK-independent IKKalpha homodimer activity. The consequent NF-kappaB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-alpha genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kappaB activity, leading to differential NF-kappaB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis.

Animals↗
PubMed2003

Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma.

Notch and basic helix-loop-helix E2A pathways specify cell fate and regulate neoplastic transformation in a variety of cell types. Whereas Notch enhances tumorigenesis, E2A suppresses it. However, whether and how Notch and E2A interact functionally in an integrative mechanism for regulating neoplastic transformation remains to be understood. It has been shown that Notch3-induced T-cell leukaemia is abrogated by the inactivation of pTalpha/pre-T-cell antigen receptor (pre-TCR). We report here that Notch3-induced transcriptional activation of pTalpha/pre-TCR is responsible for the downregulation of E2A DNA binding and transcriptional activity. Further, the E2A messenger RNA and protein levels remain unaltered but the E2A inhibitor Id1 expression is augmented in thymocytes and T lymphoma cells derived from Notch3 transgenic mice. The increase in Id1 expression is achieved by pre-TCR-induced extracellular-signalling-regulated kinase 1/2. These observations support a model in which the upregulation of pre-TCR signalling seems to be the prerequi-site for Notch3-induced inhibition of E2A, thus leading to the development of lymphoma in Notch3 transgenic mice.

Animals↗
PubMed1996

Coordinated morphogenesis of epithelia during development of the Caenorhabditis elegans uterine-vulval connection.

Development of the nematode egg-laying system requires the formation of a connection between the uterine lumen and the developing vulval lumen, thus allowing a passage for eggs and sperm. This relatively simple process serves as a model for certain aspects of organogenesis. Such a connection demands that cells in both tissues become specialized to participate in the connection, and that the specialized cells are brought in register. A single cell, the anchor cell, acts to induce and to organize specialization of the epidermal and uterine epithelia, and registrates these tissues. The inductions act via evolutionarily conserved intercellular signaling pathways. The anchor cell induces the vulva from ventral epithelial cells via the LIN-3 growth factor and LET-23 transmembrane tyrosine kinase. It then induces surrounding uterine intermediate precursors via the receptor LIN-12, a founding member of the Notch family of receptors. Both signaling pathways are used multiple times during development of Caenorhabditis elegans. The outcome of the signaling is context-dependent. Both inductions are reciprocated. After the anchor cell has induced the vulva, it stretches toward the induced vulval cells. After the anchor cell has induced specialized uterine intermediate precursor cells, it fuses with a subset of their progeny.

Animals↗
PubMed2002

Differential expression of Notch genes in human osteoblastic cells.

Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types. In the present study we investigated the expression of four Notch genes in primary human osteoblasts and in human osteoblastic osteosarcoma cell line SaOS-2 by RT-PCR. We found a strong constitutive expression of Notch-1 and a weak constitutive expression of Notch-2 in both cell types. After stimulation with Dexamethasone or Vitamin D(3), two factors known to induce differentiation in osteogenic cells, both Notch receptors were downregulated, however, with a different time course. Notch-1 and Notch-2 showed a transient induction after 2 days and a decrease after 7 days in osteoblasts and after 28 days in SaOS-2 cells. Notch-4 expression could only be detected after stimulation with Dexamethasone and Vitamin D(3). However, in osteoblasts a transient induction after 2 days could be detected in osteoblasts, whereas Notch-4 expression increased after 14 and 28 days in SaOS-2 cells. In contrast, Notch-3 was not expressed in human osteoblasts and SaOS-2 osteosarcoma cells. These data show, that Notch genes are expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors.

Cell Differentiation↗
PubMed2005

Control of cell proliferation in the Drosophila eye by Notch signaling.

Cell proliferation in animals must be precisely controlled, but the signaling mechanisms that regulate the cell cycle are not well characterized. A regulated terminal mitosis, called the second mitotic wave (SMW), occurs during Drosophila eye development, providing a model for the genetic analysis of proliferation control. We report a cell cycle checkpoint at the G1-S transition that initiates the SMW, and we demonstrate that Notch signaling is required for cells to overcome this checkpoint. Notch triggers the onset of proliferation by multiple pathways, including the activation of dE2F1, a member of the E2F transcription factor family. Delta to Notch signaling derepresses the inhibition of dE2F1 by RBF, and Delta expression depends on the secreted proteins Hedgehog and Dpp. Notch is also required for the expression of Cyclin A in the SMW.

Animals↗
PubMed2004

NGF controls dendrite development in hippocampal neurons by binding to p75NTR and modulating the cellular targets of Notch.

Notch and neurotrophins control neuronal shape, but it is not known whether their signaling pathways intersect. Here we report results from hippocampal neuronal cultures that are in support of this possibility. We found that low cell density or blockade of Notch signaling by a soluble Delta-Fc ligand decreased the mRNA levels of the nuclear targets of Notch, the homologues of enhancer-of-split 1 and 5 (Hes1/5). This effect was associated with enhanced sprouting of new dendrites or dendrite branches. In contrast, high cell density or exposure of low-density cultures to NGF increased the Hes1/5 mRNA, reduced the number of primary dendrites and promoted dendrite elongation. The NGF effects on both Hes1/5 expression and dendrite morphology were prevented by p75-antibody (a p75NTR-blocking antibody) or transfection with enhancer-of-split 6 (Hes6), a condition known to suppress Hes activity. Nuclear translocation of NF-kappaB was identified as a link between p75NTR and Hes1/5 because it was required for the up-regulation of these two genes. The convergence of the Notch and p75NTR signaling pathways at the level of Hes1/5 illuminates an unexpected mechanism through which a diffusible factor (NGF) could regulate dendrite growth when cell-cell interaction via Notch is not in action.

Active Transport, Cell Nucleus↗
PubMed2005

Functional conservation of Notch1 and Notch2 intracellular domains.

The Notch receptor is a key component of a highly conserved signaling pathway that regulates cell fate determination during development. In Drosophila, where Notch signaling was first identified and studied, there is only one Notch receptor. In contrast, mammals have four Notch receptor genes, Notch1-4. Notch1 and Notch2 are both required for embryo viability, are widely expressed in mammals, and are structurally conserved. It is presently unknown if these two receptors are functionally redundant or if they have unique capabilities related to differences in their amino acid sequences. In contrast to the rest of the molecule, the amino acid sequences of a large region of the Notch intracellular domain are not highly conserved and thus may be able to interact with distinct transcription factors and mediate the expression of different sets of genes. To determine if the function of this region is conserved, the last 426 amino acids of the Notch2 receptor have been replaced with the corresponding region of Notch1 in mice by using gene targeting. We have determined that even though the amino acid sequences of this region are only 37% identical (137/426), the C-terminal region of the Notch1 intracellular domain can functionally replace that of Notch2 in vivo.

Alleles↗
PubMed2000

Fringe is a glycosyltransferase that modifies Notch.

Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.

Animals↗
PubMed2006

Differentiation of embryonic stem cells conditionally expressing neurogenin 3.

Expression of the proendocrine gene neurogenin 3 (Ngn3) is required for the development of pancreatic islets. To better characterize the molecular events regulated by Ngn3 during development, we have determined the expression profiles of murine embryonic stem cells (mESCs) uniformly induced to overexpress Ngn3. An mESC line was created in order to induce Ngn3 by adding doxycycline to the culture medium. Genome-wide microarray analysis was performed to identify genes regulated by Ngn3 in a variety of contexts, including undifferentiated ESCs and differentiating embryoid bodies (EBs). Genes regulated by Ngn3 in a context-independent manner were identified and analyzed using systematic gene ontology tools. This analysis revealed Notch signaling as the most significantly regulated signaling pathway (p = .009). This result is consistent with the hypothesis that Ngn3 expression makes the cell competent for Notch signaling to be activated and, conversely, more sensitive to Notch signaling inhibition. Indeed, EBs induced to express Ngn3 were significantly more sensitive to gamma-secretase inhibitor-mediated Notch signaling inhibition (p < .0001) when compared with uninduced EBs. Moreover, we find that Ngn3 induction in differentiating ESCs results in significant increases in insulin, glucagon, and somatostatin expression.

Animals↗
PubMed2026

Development and preclinical evaluation of a decoy DLL4-encoding oncolytic HSV-1 for high-grade glioma.

Preclinical and clinical investigation of oncolytic HSV-1 (oHSV) treatment for cancer has indicated increased Notch signaling in tumors after treatment. Since Notch activation often heralds cancer cell stemness, angiogenesis, and invasion, the induction of this pathway after oHSV virotherapy can support tumor growth and limit response to virotherapy. Here, we evaluated the impact of blocking DLL4, a Notch ligand, on virotherapy. Matched tumor biopsies pre- and post-oHSV (CAN-3110, NCT03152318) treatment revealed an induction of DLL4 post-therapy. We observed that expression of a recombinant soluble decoy DLL4 (sDLL4) could block Notch activation in tumor cells. Thus, we engineered an oHSV vector designed to encode soluble DLL4 (OVsDLL4) to block ligand-mediated Notch signaling. RNA sequencing and gene set enrichment analysis revealed that, relative to control oHSV, OVsDLL4 blocked Notch and sprouting angiogenesis pathways after treatment. Despite slower virus replication in vitro, OVsDLL4 cytotoxicity remained effective against tumor cells. Transcriptome profiling also indicated a significant dysregulation of metabolic pathways related to oxidative phosphorylation and glutathione metabolism, in accordance with increased oxygen consumption observed by Seahorse analysis in cells expressing sDLL4. OVsDLL4-treated cells further showed increased reactive oxygen species relative to control oHSV-treated cells. Co-culture of infected tumor cells with immune cells revealed that OVsDLL4 treatment polarized them toward an inflammatory phenotype. In vivo, the therapeutic efficacy of OVsDLL4 was underscored, as treatment of glioma-bearing mice resulted in reduced tumor burden and prolonged survival.

Journal Article↗
PubMed2006

A complex oscillating network of signaling genes underlies the mouse segmentation clock.

The segmental pattern of the spine is established early in development, when the vertebral precursors, the somites, are rhythmically produced from the presomitic mesoderm. Microarray studies of the mouse presomitic mesoderm transcriptome reveal that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the notch-fibroblast growth factor and Wnt pathways during each cycle suggests that coordinated regulation of these three pathways underlies the clock oscillator.

Algorithms↗
PubMed2001

Notch signalling in the regulation of peripheral immunity.

Notch signalling plays a critical role in embryogenesis, influencing the differentiation and growth of a variety of cell types across the species. In the mammalian immune system, Notch signalling operates at various levels; it controls the differentiation of haematopoietic stem cells and directs the early development of the T and B-cell lineages. It is also involved in the maturation of both CD4+ and CD8+ T cells in the thymus. The biological activities of this pathway extend beyond lymphocyte ontogeny; recent evidence has shown that it also contributes to the regulation of the peripheral immune system through its ability to influence cell survival and growth. In fulfilling this function, Notch signalling appears to act in conjunction with defined immunological signals such as cytokines, T-cell antigen receptor and co-stimulatory receptor-mediated signalling. In this review we discuss the potential of the Notch signalling pathway in the maintenance of homeostasis within the immune system affecting both peripheral tolerance and the negative feedback controlling productive immunity. The therapeutic manipulation of this pathway is likely to have broad application in a range of immunologically based diseases.

Animals↗
PubMed1996

The neurogenic genes egghead and brainiac define a novel signaling pathway essential for epithelial morphogenesis during Drosophila oogenesis.

Notch (N) and other neurogenic genes have been implicated in two fundamental processes, lateral specification of cell fates, and epithelial development. Previous studies have suggested that the neurogenic gene brainiac (brn) is specifically required for epithelial development (Goode, S., Morgan, M., Liang, Y-P. and Mahowald, A. P. (1996). Dev. Biol. 178, 35-50). In this report we show that egghead (egh), a gene with phenotypes identical to brn, encodes for a novel, putative secreted or transmembrane protein. We describe the role of egh and brn germline function in the morphogenesis of the follicular epithelium from the time it is born through the time that it migrates towards the oocyte late in oogenesis. By comparing the function of germline egh and brn to N during oogenesis, we have obtained direct evidence for the involvement of Notch in maintenance of the follicle cell epithelium, and the specificity of brn and egh in epithelial development during oogenesis. The most striking phenotype observed for all three genes is a loss of apical-basal polarity and accumulation of follicular epithelial cells in multiple layers around the oocyte. The spatiotemporal onset of this adenoma-like phenotype correlates with the differential accumulation of egh transcripts in the oocyte at stage 4 of oogenesis. In contrast to N, we find that brn and egh are essential for the organization, but not specification, of stalk and polar cells. The expression patterns and functional requirements of brn, egh, and N lead us to propose that these genes mediate follicular morphogenesis by regulating germline-follicle cell adhesion. This proposal offers explanations for (1) the involvement of egh and brn in N-mediated epithelial development, but not lateral specification, (2) why brn and egh embryonic neurogenic phenotypes are not as severe as N phenotypes, and (3) how egh and brn influence Egfr-mediated processes. The correlation between the differential expression of egh in the oocyte and the differential requirement for brn, egh, and N in maintaining the follicular epithelium around the oocyte, suggests that Egghead is a critical component of a differential oocyte-follicle cell adhesive system.

Amino Acid Sequence↗
PubMed2001

Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila.

Notch is the receptor for a conserved signaling pathway that regulates numerous cell fate decisions during development [1]. Signal transduction involves the presenilin-dependent intracellular processing of Notch and the nuclear translocation of the intracellular domain of Notch, NICD [2-6]. NICD associates with Suppressor of Hairless [Su(H)], a DNA binding protein, and Mastermind (Mam), a transcriptional coactivator [7-9]. In the absence of Notch signaling, Su(H) acts as a transcriptional repressor [10, 11]. Repression by Su(H) is relieved by the activation of Notch [12-16]. In the Drosophila embryo, this transcriptional switch from repression to activation is important for patterning the expression of the single-minded (sim) gene along the dorsoventral axis [12]. Here, we investigate the mechanisms by which Su(H) inhibits the expression of Notch target genes in Drosophila. We show that Hairless, an antagonist of Notch signaling [17-19], is required to repress the transcription of the sim gene. Hairless forms a DNA-bound complex with Su(H). Furthermore, it directly binds the Drosophila C-terminal Binding Protein (dCtBP), which acts as a transcriptional corepressor. The dCtBP binding motif of Hairless is essential for the function of Hairless in vivo. We propose that Hairless mediates transcriptional repression by Su(H) via the recruitment of dCtBP.

Alcohol Oxidoreductases↗
PubMed2002

Notch and Wingless modulate the response of cells to Hedgehog signalling in the Drosophila wing.

During Drosophila wing development, Hedgehog (Hh) signalling is required to pattern the imaginal disc epithelium along the anterior-posterior (AP) axis. The Notch (N) and Wingless (Wg) signalling pathways organise the dorsal-ventral (DV) axis, including patterning along the presumptive wing margin. Here, we describe a functional hierarchy of these signalling pathways that highlights the importance of competing influences of Hh, N, and Wg in establishing gene expression domains. Investigation of the modulation of Hh target gene expression along the DV axis of the wing disc revealed that collier/knot (col/kn), patched (ptc), and decapentaplegic (dpp) are repressed at the DV boundary by N signalling. Attenuation of Hh signalling activity caused by loss of fused function results in a striking down-regulation of col, ptc, and engrailed (en) symmetrically about the DV boundary. We show that this down-regulation depends on activity of the canonical Wg signalling pathway. We propose that modulation of the response of cells to Hh along the future proximodistal (PD) axis is necessary for generation of the correctly patterned three-dimensional adult wing. Our findings suggest a paradigm of repression of the Hh response by N and/or Wnt signalling that may be applicable to signal integration in vertebrate appendages.

Animals↗