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PubMed2025

A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization.

The ubiquitous Notch receptor signalling network is essential for tissue growth and maintenance. Operationally, receptor activity is regulated by two principal, counterposed mechanisms: intercellular Notch transactivation triggered by interactions between receptors and ligands expressed in neighbouring cells; intracellular cis inhibition mediated by ligands binding to receptors expressed in the same cell. Moreover, different Notch receptor/ligand combinations are known to elicit distinct molecular and cellular responses, and together, these phenomena determine the strength, the duration and the specificity of Notch receptor signalling. To date, it has been assumed that these processes involve discrete ligand homomers and not heteromeric complexes composed of more than one ligand species. In this study, we explore the molecular basis of the opposing actions of the Notch ligands, DLL4 and JAG1, which control angiogenic sprouting. Through a combination of experimental approaches and mathematical modelling, we provide evidence that two mechanisms could underpin this process: 1) DLL4 rather than JAG1 induces efficient Notch1 receptor transactivation; 2) JAG1 directly blocks DLL4-dependent cis-inhibition of Notch signalling through the formation of a JAG1/DLL4 complex. We propose a new model of Notch signalling that recapitulates the formation of tip and stalk cells, which is necessary for sprouting angiogenesis.

Signal Transduction↗
PubMed2005

Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis.

BACKGROUND: The interaction of Notch receptors with their transmembrane ligands Delta and Jagged plays an important role not only in the organization of a variety of tissues but also in several genetic disorders and cancer development. The functional involvement of the Notch signaling in rheumatoid arthritis (RA) has been reported previously, but the expression profile of Notch-related molecules, as well as their relation with clinicopathological parameters, remains unclear. METHODS: In this study, we analyzed the immunohistochemical staining pattern of four Notch receptors (Notch1-4) and their ligands (Delta1 and Jagged1) in 14 synovial tissues obtained from 14 RA patients. RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively. Notch1, Notch3, Delta1, and Jagged1 were overexpressed in the synovial lining and sublining cells on synovial hyperplastic lesions in all samples. Notch1 expression was also observed in T and B lymphocytes of lymphoid follicles independently. Notch1 and Notch3 expression overlapped with that of Jagged1, as determined by confocal microscopy. Activation of Notch1 signaling in the RA synovium was identified using a specific antibody to the cleaved form of Notch1. The expression of these molecules did not show any correlation with clinicopathological parameters. CONCLUSIONS: Our results suggest that Notch signaling is activated in RA synovium but does not necessarily reflect the pathological condition of RA.

Adolescent↗
PubMed2000

Localisation of members of the notch system and the differentiation of vibrissa hair follicles: receptors, ligands, and fringe modulators.

Hair vibrissa follicle morphogenesis involves several cell segregation phases, in the dermis as well as in the epidermis. The expression of Notch-related genes, which are well established mediators of multiple cell segregation events in Drosophila development, was studied by in situ hybridisation during embryonic mouse vibrissa follicle morphogenesis and the first adult hair cycle. The results show that two receptors, Notch1 and -2, three ligands, Delta1, Serrate1, and -2, and the three Fringe regulators, Lunatic, Manic, and Radical, are expressed in different locations and morphogenetic stages. First, the appearance of hair vibrissa primordia involves the expression of complementary patterns of Notch2, Delta1, and Lunatic Fringe in the dermis and of Notch1, Serrate2, and Lunatic Fringe in the epidermis. Second, this expression pattern is no longer found after stage 3 in the dermis. Meanwhile, in the epidermis, the expression of Notch1, Serrate2, and Lunatic Fringe before the formation of the placode may be involved in determining two populations of epidermal cells in the developing follicle. Third, complementary expression patterns for Notch1, Manic, and Lunatic Fringe, as well as Serrate1 and -2 as previously shown (Powell et al., 1998), are progressively established from stage 4 of embryonic development both in the outer root sheath and in the hair matrix. These patterns are consistent with the one found in the adult anagen phase. During the hair vibrissa cycle, Notch1 and Manic Fringe display temporal and spatial changes of expression, suggesting that they may intervene as modulators of trichocyte activities.

Animals↗
PubMed2002

Expression of Notch pathway components in fetal and adult mouse small intestine.

Cell-to-cell communication mediated by the evolutionary conserved Notch signalling pathway regulates cell fate decisions and patterning in various tissues in invertebrates and vertebrates (Science 284 (1999) 770). In mouse, four Notch receptors, five ligands of the delta and Serrate types, three fringe glycosyltransferases that modify Notch, and a growing number of direct transcriptional targets of Notch are known. Mutational analysis of Hes1 (Nat. Genet. 24 (2000) 36) and Math1 (Science 294 (2001) 2155) have implicated Notch signalling in the regulation of intestinal epithelium development and homeostasis. Here, we describe the expression of the genes encoding the murine Notch receptors (Notch1-4), the ligands (delta1, 3, 4 and Jagged1, 2), the modifying glycosyltransferases of the fringe family (Lfng, Mfng, Rfng) and four Hes genes (Hes1, 5, 6, 7) in the mouse small intestine during fetal (E13.5 and E18.5) and postnatal (P25) development. All analyzed Notch pathway components were expressed in the intestine, although at different levels and with varying spatial and temporal distribution, consistent with roles of Notch signalling at various stages of intestinal development and renewal.

Animals↗
PubMed2006

Expression of the Notch signaling pathway and effect on exocrine cell proliferation in adult rat pancreas.

When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when exocrine pancreatic cells are isolated and cultured. We demonstrate that under these experimental conditions the exocrine acinar cells lose their differentiated characteristics: expression of the acinar transcription factors p48/Ptf1alpha and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic exocrine cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the cell-cycle regulator p21Cip1. This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion, we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic exocrine cells. The latter may be important in protection from neoplastic transformation.

Animals↗
PubMed2006

Pivotal role of Notch signaling in regulation of erythroid maturation and proliferation.

Notch signaling plays an important role in cell fate decisions in developmental systems. To clarify its role in committed hematopoietic progenitor cells, we investigated the effects of Notch signaling in erythroid colony forming cells (ECFCs) generated from peripheral blood. ECFCs express Notch receptors, Notch1 and Notch2, and Notch ligands Delta1, Delta4, and Jagged1. When we assayed the effects of Notch ligands on erythroid maturation by flow cytometry, we found that immobilized Delta1 and immobilized Delta4 in particular inhibited maturation, whereas Jagged1 had no effect. In addition, Delta4 inhibited proliferation without reducing cell viability. Increases in expression levels of the Notch target gene hairy enhancer of split (HES) -1 were evident by real-time PCR after stimulation with immobilized Delta4. The effect of soluble Delta4 on expression of HES-1 was less pronounced than that seen with the immobilized form, indicating that all surface-bound ligands are important for effective signal transduction. When ECFCs were cultured in the presence of soluble Delta4 at a low cell concentration, erythroid maturation was slightly inhibited, but at a high concentration, maturation was promoted via competition of soluble Delta4 with endogenous ligands. These results indicate a pivotal role of Notch signaling in regulating erythroid maturation and proliferation, and further suggest that cell-cell interactions modulate growth of erythroid progenitor cells via Notch system.

Base Sequence↗
PubMed1999

The Notch/Jagged pathway inhibits proliferation of human hematopoietic progenitors in vitro.

The cell surface receptor Notch1 is expressed on CD34+ hematopoietic precursors, whereas one of its ligands, Jagged1, is expressed on bone marrow stromal cells. To examine the role of Notch signaling in early hematopoiesis, human CD34+ cells were cultured in the presence or absence of exogenous cytokines on feeder layers that either did or did not express Jagged1. In the absence of recombinant growth factors, Jagged1 decreased myeloid colony formation by CD34+ cells, as well as 3H-thymidine incorporation and entry into S phase. In the presence of a strong cytokine signal to proliferate and mature, (interleukin 3 [IL-3] and IL-6, stem cell factor [SCF], and G-CSF), Jagged1 did not significantly alter either the fold expansion or the types of colonies formed by CD34+ cells. However, in the presence of SCF alone, Jagged1 increased erythroid colony formation twofold. These results demonstrate that Notch can modulate a growth factor signal, and that in the absence of growth factor stimulation, the Jagged1-Notch pathway preserves CD34+ cells in an immature state.

3T3 Cells↗
PubMed1996

Mesodermal development in mouse embryos mutant for fibronectin.

Three independent mutations were made by homologous recombination in two different regions of the fibronectin (FN) gene; all three appeared to be functional null mutations. The embryonic lethal phenotypes of these mutations were indistinguishable; all three FN mutant strains show mesodermal defects and fail to develop notochord or somites. Nevertheless analysis with lineage markers (Brachyury, sonic hedgehog, Notch-1, and mox-1) showed that both the notochord and the somite lineages were induced at the correct times and places. Furthermore, notochord precursor cells showed extensive cell migration in the absence of FN. However, neither notochord nor somites condensed properly in the absence of FN. These results show that specification of notochordal and somitic mesodermal lineages and significant cell migration are independent of fibronectin but that correct morphogenesis of these structures is FN-dependent.

Animals↗
PubMed1999

Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds.

Strikingly increased expression of notch-1 has been demonstrated in several human malignancies and pre-neoplastic lesions. However, the functional consequences of notch-1 overexpression in transformed cells remain unclear. We investigated whether endogenously expressed notch-1 controls cell fate determination in mouse erythroleukemia (MEL) cells during pharmacologically induced differentiation. We found that notch-1 expression is modulated during MEL cell differentiation. Premature downregulation of notch-1 during differentiation, by antisense S-oligonucleotides or by enforced expression of antisense notch-1 mRNA, causes MEL cells to abort the differentiation program and undergo apoptosis. Downregulation of notch-1 expression in the absence of differentiation inducer increases the likelihood of spontaneous apoptosis. We conclude that in MEL cells, endogenous notch-1 expression controls the apoptotic threshold during differentiation and growth. In these cells, notch-1 allows differentiation by preventing apoptosis of pre-committed cells. This novel function of notch-1 may play a role in regulating apoptosis susceptibility in notch-1 expressing tumor cells.

Acetamides↗
PubMed2000

Notch-1 activation by familial Alzheimer's disease (FAD)-linked mutant forms of presenilin-1.

We prepared a cleavage site-directed antibody against Notch-1, that specifically recognized the cleaved Notch-1 intracellular domain (NICD). To assess Notch-1 processing and its nuclear localization in familial Alzheimer's disease (FAD)-linked presenilin-1 (PS-1) mutants, we overexpressed wild type, M146V, A246E, C410Y, or deltaE9 PS-1 mutant with a membrane-bound Notch-1 in a PS-1-deficient cell line. On Western blot and immunocytochemical analyses using the NICD specific antibody, M146V and A246E mutants showed the comparable levels of Notch-1 processing and nuclear localizing activities to wild type PS-1 whereas C410Y and deltaE9 mutants failed to show these activities. These results suggest that the loss or partial loss of PS-1 activities in Notch-1 proteolysis and its nuclear translocation may be irrelevant for the neuropathology of Alzheimer's disease.

3T3 Cells↗
PubMed2000

Platelet-derived growth factor and basic fibroblast growth factor regulate cell proliferation and the expression of notch-1 receptor in a new oligodendrocyte cell line.

We generated a new cell line, N38, by conditionally immortalizing mouse oligodendrocytes (OLs) at early stages of maturation. The morphology and marker expression pattern suggest N38 cells are similar to immature OLs. N38 cells were sensitive to changes in serum concentrations, and forcing the cells to differentiate in low serum at 39 degrees C significantly decreased the survival of the cells. Importantly, addition of PDGFaa, bFGF or astrocyte-conditioned medium had protective effects on the cells, by increasing cell proliferation but not cell differentiation. This effect was receptor-mediated. Exposure of N38 cells to differentiating signals such as retinoic acid did not cause further differentiation of the cells. The N38 cell line expresses the vertebrate homolog of the Drosophila notch-1 receptor, a molecule that appears to regulate OL differentiation. Notch-1 receptor was homogeneously distributed in the somas of N38 cells. Incubation of N38 cells with either PDGFaa or bFGF, however, induced a polarized distribution of the receptor in the majority of the cells as well as an upregulation of receptor protein levels. The upregulation of molecules, such the notch-1 receptor, in pathways that control differentiation might be an important mechanism for keeping OL precursors in an undifferentiated state during their exit of the germinal layer and migration in the developing central nervous system. This OL cell line might constitute a suitable model for studies of regulatory mechanisms at this stage of OL differentiation.

Animals↗
PubMed2001

Role of Notch-1 intracellular domain in activation of rheumatoid synoviocytes.

OBJECTIVE: Notch family proteins are transmembrane receptors that control cell fate and proliferation. Rheumatoid arthritis (RA) is characterized by activation and abnormal proliferation/differentiation of synoviocytes. We examined the expression of Notch-1 and its role in the activation of RA synoviocytes. METHODS: The expression of Notch-1 protein was detected by a specific antibody raised against the Notch-1 intracellular domain. Notch-1 messenger RNA (mRNA) expression in synoviocytes was analyzed by Northern blotting. Notch-1 protein expression was confirmed by Western blotting with anti-Notch-1 antibody. To analyze the role of Notch-1 in synoviocyte proliferation, we examined the effects of antisense Notch-1 oligonucleotides (ODNs) and MW167, a gamma-secretase inhibitor. RESULTS: Notch-1 protein and mRNA were detected in synovium from all study subjects. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 antibody, whereas there was predominantly cytoplasmic staining of normal and osteoarthritis (OA) synoviocytes. Western blotting showed a distinct approximately 63-kd protein detected by anti-Notch-1 antibody in nuclear extracts from RA synoviocytes, indicating that nuclear staining of RA synovium and synoviocytes is likely to be the result of nuclear localization of Notch-1 intracellular domain (NICD). Furthermore, tumor necrosis factor alpha (TNFalpha) increased NICD nuclear translocation in a dose-dependent manner. Antisense Notch-1 ODNs partially blocked the proliferation of RA synoviocytes and inhibited TNFalpha-induced proliferation in both OA and RA synoviocytes. In addition, gamma-secretase inhibitor, which blocks the production of NICD, also inhibited TNFalpha-induced proliferation of RA synoviocytes. CONCLUSION: Our results demonstrate the expression of Notch-1 in synoviocytes and the presence of Notch-1 fragment in the nuclei of RA synoviocytes and suggest the involvement of Notch-1 signaling in the TNFalpha-induced proliferation of RA synoviocytes.

Amyloid Precursor Protein Secretases↗
PubMed2006

Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish.

Vascular endothelial growth factor-receptors (VEGF-Rs) are pivotal regulators of vascular development, but a specific role for these receptors in the formation of heart valves has not been identified. We took advantage of small molecule inhibitors of VEGF-R signaling and showed that blocking VEGF-R signaling with receptor selective tyrosine kinase inhibitors, PTK 787 and AAC 787, from 17-21 hr post-fertilization (hpf) in zebrafish embryos resulted in a functional and structural defect in cardiac valve development. Regurgitation of blood between the two chambers of the heart, as well as a loss of cell-restricted expression of the valve differentiation markers notch 1b and bone morphogenetic protein-4 (bmp-4), was readily apparent in treated embryos. In addition, microangiography revealed a loss of a definitive atrioventricular constriction in treated embryos. Taken together, these data demonstrate a novel function for VEGF-Rs in the endocardial endothelium of the developing cardiac valve.

Animals↗
PubMed2006

Notch 2 and Notch 1/3 segregate to neuronal and glial lineages of the developing olfactory epithelium.

The murine olfactory epithelium (OE) generates olfactory receptor neurons (ORNs) throughout development and into adulthood, but only a few of the factors regulating olfactory neuro- and glio-genesis have been delineated. Notch receptors maintain CNS neuronal progenitors and drive glial differentiation, and the Notch effectors Hes 1 and 5 are expressed in the OE, but the Notch receptors that stimulate Hes gene activation in defined lineages during OE development have not been determined. Here, we first use RT-PCR to reveal which Notch receptors and ligands are expressed in the developing and adult OE. This is followed by immunofluorescent detection, combined with lineage-specific markers to define the stage-specific developmental expression of different Notch family members. We show that throughout development, Notch 1 and 3 are expressed in cells retained within the lamina propria, where Notch 3 is expressed in olfactory ensheathing cells (OECs). In contrast, Notch 2 is expressed in apical embryonic and early postnatal OE neuronal progenitors. In postnatal and adult OE, Notch 1 is expressed predominantly in Bowman's glands, and Notch 2 in sustentacular cells. Notch 2 and Notch 1/3 may, therefore, have different roles in the commitment and differentiation of neuronal and glial lineages of the OE during development, and the maintenance of non-neuronal phenotypes postnatally.

Animals↗
PubMed2006

The molecular setup of the avian head mesoderm and its implication for craniofacial myogenesis.

The head mesoderm is the mesodermal tissue on either side of the brain, from forebrain to hindbrain levels, and gives rise to the genuine head muscles. Its relatedness to the more posterior paraxial mesoderm, the somites, which generate the muscles of the trunk, is conversely debated. To gain insight into the molecular setup of the head mesoderm, its similarity or dissimilarity to the somitic mesoderm, and the implications of its setup for the progress of muscle formation, we investigated the expression of markers (1) for mesoderm segmentation and boundary formation, (2) for regional specification and somitogenesis and (3) for the positive and negative control of myogenic differentiation. We show that the head mesoderm is molecularly distinct from somites. It is not segmented; even the boundary to the first somite is ill-defined. Importantly, the head mesoderm lacks the transcription factors driving muscle differentiation while genes suppressing differentiation and promoting cell proliferation are expressed. These factors show anteroposteriorly and dorsoventrally regionalised but overlapping expression. Notably, expression extends into the areas that actively contribute to the heart, overlapping with the expression of cardiac markers.

Aldehyde Oxidoreductases↗
PubMed2004

Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration.

The Notch/Jagged signaling pathway is important for cellular differentiation and proliferation. Its dysfunction is associated with human pathologies in several tissues including liver. Point mutations in Jagged-1 gene are the cause for Alagille syndrome, associated with paucity of intrahepatic bile ducts. To determine the putative role of the trans-membrane receptor Notch and its ligand Jagged-1 in liver regeneration, we investigated the expression of Notch and Jagged-1 in rat liver following 2/3 partial hepatectomy. Immunohistochemical staining of normal rat liver showed that Notch was expressed in hepatocytes, bile duct cells and endothelial cells, whereas Jagged-1 was expressed in bile duct cells and hepatocytes. Both Notch-1 and Jagged-1 proteins were upregulated in hepatocytes after partial hepatectomy up to day 4. After partial hepatectomy, nuclear translocation of the intracellular cytoplasmic domain of Notch (NICD) increased and peaked within 15 minutes, indicating the activation of Notch. Expression of the Notch-dependent target gene (HES-1) expression increased within 30-60 minutes. Addition of recombinant Jagged-1 protein to primary cultures of hepatocytes stimulated hepatocyte DNA synthesis. Furthermore, injection of silencing RNA for Notch and Jagged-1 to livers 2 days before partial hepatectomy significantly suppressed proliferation of hepatocytes at days 2 to 4 of the regenerative response. In conclusion, Notch/Jagged signaling pathway is activated during liver regeneration and is potentially contributing to signals affecting cell growth and differentiation.

Animals↗