SEARCH · Search PubMed

Results for “Notch”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed2005

Notch in the pathway: the roles of Notch signaling in neural crest development.

Here, we review recent studies that suggest that Notch signaling has two roles during neural crest development: first in establishing the neural crest domain within the ectoderm via lateral induction and subsequently in diversifying the fates of cells that arise from the neural crest via lateral inhibition. The first of these roles, specification of neural crest via lateral induction, has been explored primarily in the cranial neural folds from which the cranial neural crest arises. Evidence for such a role has thus far only been obtained from chick and frog; results from these two species differ, but share the feature that Notch signaling regulates genes that are expressed by cranial neural crest through effects on expression of Bmp family members. The second of these roles, diversification of neural crest progeny via lateral inhibition, has been identified thus far only in trunk neural crest. Evidence from several species suggests that Notch-mediated lateral inhibition functions in multiple episodes in this context, in each case inhibiting neurogenesis. In the 'standard' mode of lateral inhibition, Notch promotes proliferation and in the 'instructive' mode, it promotes specific secondary fates, including cell death or glial differentiation. We raise the possibility that a single molecular mechanism, inhibition of so-called proneural bHLH genes, underlies both modes of lateral inhibition mediated by Notch signaling.

Animals↗

PubMed2005

Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP.

Down syndrome (DS) patients suffer from mental retardation, but also display enhanced beta-APP production and develop cortical amyloid plaques at an early age. As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes. Using pull-down studies we could demonstrate interaction of APP with Notch1, suggesting that these transmembrane proteins form heterodimers, but independent of gamma-secretase. We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65. Furthermore, activated Notch1 can trans-activate an APP target gene, Kai1, and vice versa, activated APP can trans-activate the classical Notch target gene Hes1. These data suggest that Notch expression is activated in Down syndrome, possibly through cross-talk with APP signaling. This interaction might affect brain development, since the Notch pathway plays a pivotal role in neuron-glia differentiation.

Adult↗

PubMed2001

SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.

Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40 repeats. In the case of Notch1, this block leads to an increase in Notch signaling stimulated by either an activated form of the Notch1 receptor or Jagged1-induced signaling through Notch1. Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1. The Notch4 intracellular domain bound to SEL-10, but its activity was not increased as a result of dominant-negative SEL-10 expression. SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells. We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats. When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10. Ubiquitination of Notch1 and Notch4 intracellular domains in vitro was dependent on SEL-10. Although SEL-10 interacts with the intracellular domains of both Notch1 and Notch4, these proteins respond differently to interference with SEL-10 function. Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ.

Animals↗

PubMed2005

The Notch regulator Numb links the Notch and TCR signaling pathways.

Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.

Animals↗

PubMed2002

Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects.

The Jagged and Delta family of transmembrane proteins are ligands for Notch receptors, which control the proliferation and/or differentiation of many cell lineages. Expression and localization of these ligands in the adult human liver has not been fully elucidated, nor whether dysregulation of these proteins contributes to liver disease processes. We have examined expression of the five known Notch ligands in human liver. Expression of Jagged-1 and Delta-4 mRNA was seen in normal and diseased liver tissue, whereas Jagged-2, Delta-1, and Delta-3 mRNA was undetectable. In primary liver cell isolates, Jagged-1 expression was found in all cell types, whereas Delta-4 was present in biliary epithelial and liver endothelial cells, but absent in hepatocytes. Interestingly, Jagged-1 mRNA expression was significantly up-regulated in diseased liver tissue. By immunohistochemistry, Jagged-1 expression was present on most structures in normal tissue. However in disease, strikingly strong Jagged-1 immunoreactivity was observed on many small neovessels and bile ductules. The expression of downstream modulators and effectors of Notch signaling was also detectable in purified cell isolates. This, together with aberrant Jagged-1 expression suggests that the Notch signaling pathway may play a role in the neovascularization and biliary defects observed in the liver during the development of cirrhosis.

Adult↗

PubMed2000

Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis.

OBJECTIVE: Hematopoiesis is the process by which mature blood cell types are generated from a small population of pluripotent hematopoietic stem cells. How these cells undergo fate selection, however, is not fully understood. The Notch signaling system is known to mediate cell fate decisions of multipotent precursors in a wide range of complex animals throughout development. As Notch signaling involves cell-cell interactions, we sought to determine the expression of Notch receptors, ligands, and regulators in individual cell populations along the hematopoietic differentiation pathway. MATERIALS: Described here is a single cell RT-PCR analysis of Notch1, Notch3, Notch4, Notch ligands (Dll1 and Jagged1), and Fringe gene expression in cells of the blood system. As previously described, single cell globally amplified cDNA was generated by RT-PCR from various hematopoietic precursor cells whose potential was known from sibling analysis. A precursor hierarchy slot blot was created containing these cDNAs as well as samples from maturing blood cell populations and two fibroblast cell lines. The precursor slot blot was screened with probes for each of the candidate genes. RESULTS: Macrophage precursors expressed high levels of Notch1 transcript, while maturing macrophages expressed high levels of both Notch1 and Notch4. The Jagged 1 ligand transcript was highly expressed in terminally maturing cells including mast cells and megakaryocytes. In contrast, the Manic Fringe gene was highly expressed in uncommitted bi- and tri-potential precursors as well as in committed neutrophil and macrophage precursors. CONCLUSIONS: Distinct expression patterns of Jagged1 and Manic Fringe suggest that their corresponding proteins could regulate cell fate choices during hematopoiesis and may be responsible for regulating communication between lineage compartments during hematopoietic development.

Animals↗

PubMed2004

Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity.

To examine early events in osteoblast differentiation, we analyzed the expression of about 9,400 genes in the murine MC3T3 cell line, whose robust differentiation was documented cytochemically and molecularly. The cells were stimulated for 1 and 3 days with the osteogenic stimulus containing bone morphogenic protein 2. Total RNA was extracted and analyzed by Affymetrix GeneChip oligonucleotide arrays. A regulated expression of 394 known genes and 295 expressed sequence tags was detected. The sensitivity and reliability of detection by microarrays was shown by confirming the expression pattern for 20 genes by radioactive quantitative reverse transcription-PCR. Functional classification of regulated genes was performed, defining the groups of regulated growth factors, receptors, and transcription factors. The most interesting finding was concomitant activation of transforming growth factor-beta, Wnt, and Notch signaling pathways, confirmed by strong up-regulation of their target genes by PCR. The transforming growth factor-beta pathway is activated by stimulated production of the growth factor itself, while the exact mechanism of Wnt and Notch activation remains elusive. We showed that bone morphogenic protein 2 stimulated expression of Hey1, a direct Notch target gene, in mouse MC3T3 and C2C12 cells, in human mesenchymal cells, and in mouse calvaria. Small interfering RNA-mediated inhibition of Hey1 induction led to an increase in osteoblast matrix mineralization, suggesting that Hey1 is a negative regulator of osteoblast maturation. This negative regulation is apparently achieved via interaction with Runx2: Hey1 completely abrogated Runx2 transcriptional activity. These findings identify the Notch-Hey1 pathway as a negative regulator of osteoblast differentiation/maturation, which is a completely novel aspect of osteogenesis and could point to possible new targets for bone anabolic agents.

3T3 Cells↗

PubMed1999

Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors.

Jagged1 belongs to the DSL family of ligands for Notch receptors that control the proliferation and differentiation of various cell lineages. However, little is known about the transcription factors that regulate its expression. Here, we show that Jagged1 is a Rel/NF-kappaB-responsive gene. Both c-Rel and RelA induced jagged1 gene expression, whereas a mutant defective for transactivation did not. Importantly, jagged1 transcripts were also upregulated by endogenous NF-kappaB activation and this effect was inhibited by a dominant mutant of IkappaBalpha, a physiological inhibitor of NF-kappaB. Cell surface expression of Jagged1 in c-Rel-expressing cell monolayers led to a functional interaction with lymphocytes expressing the Notch1/TAN-1 receptor. This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells. Consistent with its Rel/NF-kappaB-dependent induction, Jagged1 was found to be highly expressed in splenic B cells where c-Rel is expressed constitutively. These results demonstrate that c-Rel can trigger the Notch signaling pathway in neighboring cells by inducing jagged1 gene expression, and suggest a role for Jagged1 in B-cell activation, differentiation or function. These findings also highlight the potential for an interplay between the Notch and NF-kappaB signaling pathways in the immune system.

B-Lymphocytes↗

PubMed1997

Identification and localization of a sea urchin Notch homologue: insights into vegetal plate regionalization and Notch receptor regulation.

The specifications of cell types and germ-layers that arise from the vegetal plate of the sea urchin embryo are thought to be regulated by cell-cell interactions, the molecular basis of which are unknown. The Notch intercellular signaling pathway mediates the specification of numerous cell fates in both invertebrate and vertebrate development. To gain insights into mechanisms underlying the diversification of vegetal plate cell types, we have identified and made antibodies to a sea urchin homolog of Notch (LvNotch). We show that in the early blastula embryo, LvNotch is absent from the vegetal pole and concentrated in basolateral membranes of cells in the animal half of the embryo. However, in the mesenchyme blastula embryo LvNotch shifts strikingly in subcellular localization into a ring of cells which surround the central vegetal plate. This ring of LvNotch delineates a boundary between the presumptive secondary mesoderm and presumptive endoderm, and has an asymmetric bias towards the dorsal side of the vegetal plate. Experimental perturbations and quantitative analysis of LvNotch expression demonstrate that the mesenchyme blastula vegetal plate contains both animal/vegetal and dorsoventral molecular organization even before this territory invaginates to form the archenteron. Furthermore, these experiments suggest roles for the Notch pathway in secondary mesoderm and endoderm lineage segregation, and in the establishment of dorsoventral polarity in the endoderm. Finally, the specific and differential subcellular expression of LvNotch in apical and basolateral membrane domains provides compelling evidence that changes in membrane domain localization of LvNotch are an important aspect of Notch receptor function.

Amino Acid Sequence↗

PubMed1981

Head trauma: single-notch and double-notch audiograms.

Single-notch and double-notch sensorineural hearing losses were observed in 27 adult patients. All patients denied having a history of noise exposure, but did report at least one episode of hear trauma. Generally, the laterality and degree of hearing loss did not appear to correlate well with severity and site of head trauma, or post-traumatic symptoms. Although not all individuals suffering head trauma will yield notch audiograms, when an audiometric notch is observed the possibility of head trauma as well as other factors should be explored in the patient's history.

Adult↗

PubMed1995

[A study for predicting toxemia of pregnancy by the diastolic notch in pulsed Doppler flow velocity waveforms of the uterine arteries--quantitative analysis of the diastolic notch as uterine arterial index (UTAI)].

To investigate the ability of measurement of the diastolic notch in Doppler flow velocimetry to predict development of toxemia of pregnancy, analysis of uteroplacental and fetal blood flow waveforms was performed. The waveforms were analyzed by calculating the resistance index (RI) and the pulsatility index (PI) and were investigated whether diastolic notches existed or not. In the prospective study, the uterine arterial index (UTAI; an index introduced to evaluate the degree of diastolic notch quantitatively) was also calculated. RETROSPECTIVE STUDY: The waveforms in the uterine arteries, the umbilical artery and the fetal vessel (inferior vena cava, descending aorta and middle cerebral artery) were measured in 153 pregnant women. PROSPECTIVE STUDY: Uterine artery velocimetry was performed at 16-23 weeks' gestation in 387 pregnant women. RESULT 1: Subjects with a diastolic notch had significantly higher rates of development of toxemia of pregnancy. Indexes of the fetal blood flow waveforms had no significant correlations with the development of toxemia of pregnancy. RESULT 2: UTAI showed an equivalently high negative predictive value (98.1%) and higher positive predictive value (17.6%) than RI (98.2%, 10.2% respectively) and PI (98.7%, 12.7% respectively). CONCLUSION: UTAI measurement was more useful for predicting toxemia of pregnancy than RI or PI.

Arteries↗

PubMed1997

Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.

In both vertebrate and invertebrate development, cells are often programmed to adopt fates distinct from their neighbors. Genetic analyses in Drosophila melanogaster have highlighted the importance of cell surface and secreted proteins in these cell fate decisions. Homologues of these proteins have been identified and shown to play similar roles in vertebrate development. Fringe, a novel signalling protein, has been shown to induce wing margin formation in Drosophila. Fringe shares significant sequence homology and predicted secondary structure similarity with bacterial glycosyltransferases. Thus fringe may control wing development by altering glycosylation of cell surface and/or secreted molecules. Recently, two fringe genes were isolated from Xenopus laevis. We report here the cloning and characterization of three murine fringe genes (lunatic fringe, manic fringe and radical fringe). We find in several tissues that fringe expression boundaries coincide with Notch-dependent patterning centres and with Notch-ligand expression boundaries. Ectopic expression of murine manic fringe or radical fringe in Drosophila results in phenotypes that resemble those seen in Notch mutants.

Amino Acid Sequence↗

PubMed1997

strawberry notch encodes a conserved nuclear protein that functions downstream of Notch and regulates gene expression along the developing wing margin of Drosophila.

The dorsal/ventral (D/V) boundary functions as an organizer in the growth and patterning of the Drosophila wing disc and gives rise to the wing margin in the adult fly. Here we show that strawberry notch (sno) is a downstream component of the Notch signaling pathway and is important for the specification of this organizer. sno encodes a novel nuclear protein conserved in C. elegans, mouse, and humans. Mutations in wing margin genes interact dominantly with sno and loss of sno function results in loss of expression of wingless, vestigial, cut, and E(spl)-m8 at the D/V boundary. In regulating these genes, sno functions in close cooperation with Suppressor of Hairless and Hairless. Finally, sno has no role in lateral inhibition suggesting that it may contribute to the specificity between lateral and inductive Notch signaling pathways.

Amino Acid Sequence↗

PubMed2005

Functional redundancy of the Notch gene family during mouse embryogenesis: analysis of Notch gene expression in Notch3-deficient mice.

The Notch3 gene, a member of the Notch gene family, is expressed in a wide variety of tissues during development. We generated and analyzed Notch3-deficient mice to assess the in vivo role of the Notch3 gene. Consistent with previous observation of Krebs et al. [Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation, Genesis 37 (3) (2003) 139-143], the Notch3-/- mice were viable, fertile, and developed normally despite abundant expression of Notch3 in various embryonic tissues. We examined the details of Notch1, 2, and 4 expressions in the Notch3-/- embryos compared with those in wild-type embryos. As a result, we found that a deficiency in Notch3 did not affect the expression of Notch1, 2, and 4, and that either Notch1 or Notch2, or sometimes both, was always expressed in all Notch3-expressing tissues examined. These results support the idea that other Notch genes functionally compensate for Notch3 during embryonic development. We also surveyed the adult tissues of Notch3-/- mice and found significantly fewer thymocytes in 10-week-old mice. Therefore, the thymus might be a target tissue affected by Notch3 deficiency.

Animals↗

PubMed2006

Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch.

Complex formation between the intracellular domain of the Notch receptor (NICD) and the transcription factor CSL is indispensable for transcriptional activation. To understand how NICD displaces CSL-associated co-repressors, we have quantified the binding of different Notch1 ICD regions to a key interaction domain (the beta trefoil domain, or BTD) of human CSL. Electrophoresis, scattering, and titration calorimetry indicate that NICD and BTD combine to form a 1:1 heterodimer. Neither the Notch1 ankyrin domain (ANK) nor C-terminal region contributes binding energy towards BTD. In contrast, binding energy is attributed largely to a short segment including the conserved WFP sequence motif within the RAM region (the approximately 140 residue polypeptide segment N-terminal to the ANK domain); substitution of this motif substantially reduces affinity. Short (< or =25 residues) WFP-containing peptides encoded by the four mammalian Notch genes have similar affinities to BTD; thus, activity differences between paralogues either result from other regions of NICD and CSL or from differences in interaction with downstream components. The importance of RAM was demonstrated by the ability of a short RAM peptides to dissociate NICD:CSL interaction in cellular lysates. These results support an emerging molecular mechanism for the displacement of co-repressors from DNA-bound CSL by NICD.

Amino Acid Sequence↗

PubMed1976

[Notch effect on the fatigue strength of the denture base resin. (Part 3). Effect of reinforcement for composite material with notch (author's transl)].

The denture base which is made from the acrylic resin often occurs the fracture during function, and it is known that this fracture is mainly occured by the fatigue fracture, which is happened by the crack growth from the location of high stress. Until now, the author discussed on the fatigue properties about the specimens with semi-circular notch as the model of the remaining natural teeth, but these results are not easily applied to the design of denture base because the shape of denture base, considering its function and esthetics, is not changed. So, for the improvement of the strength of denture base, the denture base might be used the reinforcement. And, used as a trial the organic fiber as reinforcement, and their effects were investigated from the sides of the bending moment at fracture and the strain distribution occurs the fracture at the posterios palatal area, and its strength is improved 190%. And the fracture of the complete denture happens in general at the location between two central incisors, therefore this problem should be considered as the notched effect. So, reinforcing the lingual part of maxillary anterior teeth using the organic fiber, its strength is improved 53% comparing with the general complete denture. Therefore, the effects of reinforcement were enough appeared, and the improvement of the strength of denture base is very expected in dental use.

Composite Resins↗

PubMed2002

Intracellular cell-autonomous association of Notch and its ligands: a novel mechanism of Notch signal modification.

Notch (N) and its ligands, Delta (Dl) and Serrate (Ser), are membrane-spanning proteins with EGF repeats. They play an essential role in mediating proliferation and segregated differentiation of stem cells. One of the prominent features of N signal system is that its ligands are anchored to the plasma membrane, which allows the ligand/receptor association only between the neighboring cells. Various lines of evidences have verified this intercellular signal transmission, but there also have been implications that expression of Dl or Ser interferes cell-autonomously with the ability of the cell to receive N signal, implying that N and its ligands may interact in the same cell. Here, we demonstrate that N, Dl, and Ser cell-autonomously form homomeric or heteromeric complexes. The cell-autonomous heteromeric complexes are not present on the cell surface, implying that the association occurs in the endoreticulum or Golgi apparatus. Expression of Dl or Ser cell-autonomously reduces the N-mediated HES-5 promoter activity, indicating that the cell-autonomous association alters the N signal receptivity. Intracellular deletion of Dl shows elevated activity of this dominant-negative effect. In vivo overexpression study suggests that the cell-autonomous function of Dl and Ser is independent of the ligand specificity and may be modulated by Fringe (Fg), which inhibits the formation of the cell-autonomous Dl/N or Ser/N complex.

Amino Acid Motifs↗

PubMed2003

Regulation of Notch signaling by a novel mechanism involving suppressor of hairless stability and carboxyl terminus-truncated notch.

Different amounts of Suppressor of Hairless (SuH)-dependent Notch (N) signaling is often used during animal development to produce two different tissues from a population of equipotent cells. During Drosophila melanogaster embryogenesis, cells with high amounts of this signaling differentiate the larval epidermis whereas cells with low amounts, or none, differentiate the central nervous system (CNS). The mechanism by which SuH-dependent N signaling is increased or decreased in these different cells is obscure. The developing epidermis is known to get enriched for the full-length N (NFull) and the developing CNS for the carboxyl terminus-truncated N (NdeltaCterm). Results described here indicate that this differential accumulation of N receptors is part of a mechanism that would promote SuH-dependent N signaling in the developing epidermis but suppress it in the developing CNS. This mechanism involves SuH-dependent stability of NFull, NFull-dependent accumulation of SuH, stage specific stability of SuH, and NdeltaCterm-dependent loss of SuH and NFull.

Animals↗