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 1,477 records · Page 82Linked to original sources

PubMed2006

Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors.

The bone marrow and thymus, although both hemopoietic environments, induce very distinct differentiation outcomes. The former supports hemopoietic stem cell self-renewal and multiple hemopoietic lineages, while the latter supports T lymphopoiesis almost exclusively. This distinction suggests that the thymic environment acts to restrict the hemopoietic fates available to thymic immigrants. In this study, we demonstrate that the addition of the Notch ligand Delta-like-1 (Dll-1) to an in vitro system that otherwise supports myelopoiesis, greatly reduces the myelopoietic potential of stem cells or uncommitted progenitors. In contrast, committed myeloid progenitors mature regardless of the presence of Dll-1. The block in myelopoiesis is the direct result of Notch signaling within the hemopoietic progenitor, and Dll-1-induced signals cause a rapid increase in the expression of the zinc finger transcription factor GATA-2. Importantly, in the absence of GATA-2, Dll-1-induced signals fail to inhibit commitment to the myeloid fate. Taken together, our results support a role for GATA-2 in allowing Dll-1 to restrict non-T cell lineage differentiation outcomes.

Cells, Cultured↗

PubMed2003

Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals.

Recent studies indicate that nicastrin (NCT) and presenilins form functional components of a multimeric gamma-secretase complex required for the regulated intramembraneous proteolysis of Notch and beta-amyloid (Abeta) precursor protein (APP). To determine whether nicastrin is required for proteolytic processing of Notch and APP in mammals and the role of nicastrin in presenilin/gamma-secretase complex assembly, we generated nicastrin-deficient (NCT-/-) mice and derived fibroblasts from NCT-/- embryos. Nicastrin-null embryos died by embryonic day 10.5 and exhibited several patterning defects, including abnormal somite segmentation, phenotypes that are reminiscent of embryos lacking Notch1 or both presenilins. Importantly, secretion of Abeta peptides is abolished in NCT-/- fibroblasts, whereas it is reduced by approximately 50% in NCT+/- cells; the failure to generate Abeta peptides in NCT-/- cells is accompanied by destabilization of the presenilin/gamma-secretase complex and accumulation of APP-C-terminal fragments. Moreover, APP trafficking analysis in NCT-/- fibroblasts revealed a significant delay in the rate of APP reinternalization compared with that of control cells. Together, these results establish that nicastrin is an essential component of the multimeric gamma-secretase complex in mammals required for both gamma-secretase activity and APP trafficking and suggest that nicastrin may be a valuable therapeutic target for Alzheimer's disease.

Abnormalities, Multiple↗

PubMed2005

Modulation of the notch pathway for immunotherapy.

Since its initial description as a neurogenic locus in Drosophila, the Notch pathway has been shown to play a central role in cell fate decisions across species, including vertebrates, guiding the differentiation of multiple cell types. In the immune system, its function was first demonstrated during lymphopoiesis, but in recent years this pathway has been shown to still be active in peripheral T-cells. Therapeutic opportunities that could arise from the manipulation of Notch signaling in immune disorders such as autoimmunity, allergy and in cancer immunotherapy and transplantation are discussed.

Animals↗

PubMed2005

Effect of notch ligands on in vitro sensitivity to chemo-therapeutic drugs in leukemia and lymphoma cells.

The effect of the recombinant Notch ligand proteins Jagged1 and Delta1 on drug-sensitivity of leukemia and lymphoma cells was examined. Four acute myeloid leukemia (AML) cell lines were cultured in ligand-coated wells and control wells, with cytosine arabinoside (Ara-C), doxorubicin, or mitoxantrone, and nine lymphoid leukemia or lymphoma cell lines were cultured with dexamethasone. The growth was evaluated with a colorimetric assay. The drug-induced growth suppression was slightly reduced by the ligand stimulation in 4 out of 17 combinations of cells versus drugs, such as NB4 cells versus Ara-C. In the remainder, the ligands did not significantly affect the drug-sensitivity. To investigate the possible molecular mechanism of the protective effect, the influence of Jagged1 on Ara-C-induced activation of caspase-3 and PARP, and dephosphorylation of NF-kappaB was examined in NB4 cells. However, Jagged1 did not obviously affect the activation and dephosphorylation. It is known that stromal cells reduce drug-induced cytotoxicity of leukemia cells. According to our results, the role of Notch ligands in the stroma-mediated resistance seems to be minor and occurs only in a limited context. However, the ligand-coated culture-plates are more similar to the microenvironment in human bone marrow than ordinary plates. We will further examine the clinical usefulness of the drug-sensitivity test using the ligand-coated plates.

Antineoplastic Agents↗

PubMed1997

[Signalling by Notch family receptors].

From nematode to man, the transmembrane receptors of the Notch family act throughout embryonic and post-embryonic development to regulate the acquisition and/or maintenance of specific differentiative states. We will review here our current state of knowledge on Notch receptors structure and signalling activity.

Animals↗

PubMed1998

Interactions between Wingless and Notch during the assignment of cell fates in Drosophila.

A large number of observations suggest that, during Drosophila development there are close functional interactions between the activity of Notch receptor and that of a signaling molecule encoded by wingless gene. In this essay, I summarize these interactions and discuss the possibility that Wingless acts as a ligand for Notch as part of a switch that is iteratively involved in the assignation of cell fates during development.

Animals↗

PubMed2000

Notch signaling and the emergence of auditory hair cells.

OBJECTIVE: Recent insights into the mechanisms that determine a hair cell's fate have emerged from studies on invertebrate sensory organs and the avian inner ear. These mechanisms have important implications for our understanding of the possible therapeutic management of sensorineural deafness. This article reviews the current state of our knowledge regarding mammalian auditory hair cell fate specification. DESIGN: Data were obtained from the MEDLINE database and data presented at the Molecular Biology of Hearing and Deafness Meeting (Bethesda, Md, October 1998). Articles reporting information about cell fate specification and Notch and its ligands were selected. MAIN OUTCOME MEASURES: Data pertaining to cell fate mechanisms, Notch and its ligands, and application to hearing were extracted. RESULTS: The Notch/ligand mechanism is responsible for the specification of the hair cell phenotype. CONCLUSIONS: Major progress has been made in understanding this fundamental process, and its application to hair cell determination is only now being realized. Possible applications could involve the "switching" of supporting cells to hair cells, thus replenishing those hair cells damaged in sensorineural hearing loss.

Hair Cells, Auditory↗

PubMed1997

Thickness distribution of the subchondral mineralization zone of the trochlear notch and its correlation with the cartilage thickness: an expression of functional adaptation to mechanical stress acting on the humeroulnar joint?

BACKGROUND: The thickness of cortical bone and the density of cancellous bone have been shown to reflect local mechanical stress. However, little is known whether this also applies to the thickness of the subchondral mineralization zone (SMZ). Since the humeroulnar joint may be regarded as a model of bicentric load transmission, we examined the thickness distribution of the SMZ of the trochlear notch. METHODS: Fourteen trochlear notches were examined. Eight joint surfaces of these ulnae were completely divided, 4 incompletely subdivided, and 2 remained undivided. After embedding, sagittal sections were prepared. The thickness distributions of SMZ and cartilage were measured, graphically reconstructed, and the correlation between the two calculated for each joint. RESULTS: The thickness of the SMZ lies between 120 and 1,400 microns. Regular patterns were observed with ventral and dorsal maxima, with close correlations between the type of joint and the thickness distribution of the SMZ. The cartilage thickness varied between 350 and 2,000 microns. The pattern of cartilage thickness differed significantly from that of the SMZ. The mean correlation coefficient between SMZ and cartilage thickness was 0.3. CONCLUSIONS: The SMZ thickness depends upon the type of joint and appears to be an expression of the local loading history of the SMZ. The bicentric transmission of force at the humeroulnar joint is reflected in the bicentric distribution of SMZ thickness. A possible explanation for the different distributions of SMZ and cartilage could be the differing types of local mechanical stress acting on bone and cartilage, and/or the different reactions of osteocytes and chondrocytes.

Adaptation, Physiological↗

PubMed2002

Segmentation defects of Notch pathway mutants and absence of a synergistic phenotype in lunatic fringe/radical fringe double mutant mice.

The Notch signaling pathway is important in regulating formation and anterior-posterior patterning of somites in vertebrate embryos. Here we show that distinct segmentation defects are displayed in embryos mutant for the Notch pathway genes Notch1, Lunatic fringe (Lfng), Delta-like 1 (Dll1), and Delta-like 3 (Dll3). Lfng-deficient mice and Dll3-deficient mice exhibit very similar defects, and marker analysis suggests that progression of the segmentation clock is disrupted in Dll3 mutants. We also show that Radical fringe (Rfng)-deficient mice exhibit no obvious phenotypic defects. To assess whether the absence of a phenotype in Rfng-deficient mice was the result of functional redundancy with the Lfng gene, we generated Lfng/Rfng double homozygous mutant mice. These mice exhibit the skeletal defects normally observed in Lfng-deficient mice, but we detected no obvious synergistic or additive effects in the double mutant animals.

Animals↗

PubMed2021

RNA-seq Analysis of Peri-Implant Tissue Shows Differences in Immune, Notch, Wnt, and Angiogenesis Pathways in Aged Versus Young Mice.

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch, and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

AGING↗

PubMed1997

Calcium binding to tandem repeats of EGF-like modules. Expression and characterization of the EGF-like modules of human Notch-1 implicated in receptor-ligand interactions.

The Ca(2+)-binding epidermal growth factor (cbEGF)-like module is a structural component of numerous diverse proteins and occurs almost exclusively within repeated motifs. Notch-1, a fundamental receptor for cell fate decisions, contains 36 extracellular EGF modules in tandem, of which 21 are potentially Ca(2+)-binding. We report the Ca(2+)-binding properties of EGF11-12 and EGF10-13 from human Notch-1 (hNEGF11-12 and hNEGF10-13), modules previously shown to support Ca(2+)-dependent interactions with the ligands Delta and Serrate. Ca2+ titrations in the presence of chromophoric chelators, 5,5'-Br2BAPTA and 5-NBAPTA, gave two binding constants for hNEGF11-12, Kd1 = 3.4 x 10(-5) M and Kd2 > 2.5 x 10(-4) M. The high-affinity site was found to be localized to hNEGF12. Titration of hNEGF10-13 gave three binding constants, Kd1 = 3.1 x 10(-6) M, Kd2 = 1.6 x 10(-4) M, and Kd3 > 2.5 x 10(-4) M, demonstrating that assembly of EGF modules in tandem can increase Ca2+ affinity. The highest affinity sites in hNEGF11-12 and hNEGF10-13 had 10 to 100-fold higher affinity than reported for EGF32-33 and EGF25-31, respectively, from fibrillin-1, a connective tissue protein with 43 cbEGF modules. A model of hNEGF11-12 based on fibrillin-1 EGF32-33 demonstrates electronegative potential that could contribute to the higher affinity of the Ca(2+)-binding site in hNEGF12. These data demonstrate that the Ca2+ affinity of cbEGF repeats can be highly variable among different classes of cbEGF containing proteins.

Blotting, Western↗

PubMed1981

The action of the notch locus in Drosophila melanogaster. I. Effects of the notch8 deficiency on mitochondrial enzymes.

It is shown that the Notch8 deficiency in Drosophila melanogaster affects a number of enzyme activities localized in the mitochondria, such as NADH oxidase (activity of the complete respiratory chain), NADH dehydrogenase (the first step in the respiratory chain before transfer to ubiquinone), Succinate dehydrogenase and alpha-glycerophosphate dehydrogenase. The experiments reported here do not exclude the possibility of involvement of other genes in the deficiency. The effect of duplications of the Notch locus on NADH oxidase and NADH dehydrogenase suggest that the locus determines the enzyme activities. The dosage effects of the Notch locus on activity suggest that this locus contains the structural genes for these enzymes.

Animals↗

PubMed1981

The recombinational analysis of aberrations and the position of the notch locus on the polytene chromosome of Drosophila.

The recombinational analysis of heterozygotes for a point-mutant N and a deficiency N suggests that the map region approximated by the interval fa to nd2 is at the right edge of salivary band 3C7 or in the interband to the right. The map region N55ell to fa can be anywhere between the left-interband and the right edge of 3C7. We discovered that small inversions also can be used in the recombinational analysis, and the inversion data support the conclusions already described. The reactivation of latent mutability in a Notch inversion resulted in reinversion of the original aberration, followed by reversion of N to N+. From the same Notch inversion, we isolated a spontaneous deficiency superimposed upon the original aberration, which supported our hypothesis that two of our w to N deficiencies probably originated as deficiencies superimposed upon inversions.

Animals↗

PubMed1986

Anatomical variations of the semilunar notch in elbow dislocations.

The anatomical relations of the semilunar notch of the ulna were studied in radiographs, taken in a strict lateral view, from 100 patients with elbow dislocations. The results were compared with those from a control group of 150 patients without dislocation or other radiographic pathology. We found that the coronoid process and an angle (a) formed between the axis of the ulna and a line going through the tip of the coronoid process and the tip of the olecranon were significantly smaller than those in the control group (P = 0.02). The central angle of the semilunar notch was significantly larger in the dislocation group than in the control group (P = 0.009). The smaller angle (a) and larger central angle in the dislocation group are a result of a lower coronoid process, but they are also due to the prominent tip of the olecranon. The results suggest that the dislocation mechanism is partly a hyperextension, with the tip of the olecranon as the pivot point.

Disease Susceptibility↗

PubMed1985

[Plate fracture--a finite element for the calculation of notch tension around differently shaped plates].

A hole in a plate loaded by bending induces notch stresses in it's surrounding. This stress amplification depends on the shape of the hole. In the present paper this effect is studied by use of the Finite Element Method systematically. It was found that longer holes induce lower notch stresses than circular holes. Some tendency to find the optimate hole shape with lowest stresses is shown. Following this way the danger of plate failure by cracking may be reduced. The shape of the cross-section of the plate was fixed during this considerations.

Biomechanical Phenomena↗

PubMed2002

The soluble Notch ligand, Jagged-1, inhibits proliferation of CD34+ macrophage progenitors.

The Notch/Notch ligand system controls diverse cellular processes. The proteolytic cleavage generates transmembrane and soluble forms of Notch ligands. We examined the effect of a soluble Notch ligand, human Jagged-1, on human cord blood (CB) CD34+ cells, under serum-deprived conditions, using soluble human Jagged-1-immunoglobulin G1 chimera protein (hJagged-1). Soluble hJagged-1 inhibited myeloid colony formation but not erythroid-mix or erythroid colony formation, in the presence of stem cell factor (SCF), interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, thrombopoietin, and erythropoietin. Cytological analysis revealed that the decrease in myeloid colonies resulted mainly from the inhibition of macrophage colony formation. Furthermore, soluble hJagged-1 led to the inhibition of macrophage colony formation supported by M-CSF plus SCF and GM-CSF plus SCF. Delayed-addition experiments and the analysis of colony sizes demonstrated that soluble hJagged-l inhibited the growth of macrophage progenitors by acting in the early stage of macrophage development. The direct action of hJagged-1 was confirmed by the enhanced expression of the HES-1 (hairy enhancer of the split-1) gene. These results suggest that soluble hJagged-1 may regulate human hematopoiesis in the monocyte/macrophage lineage.

Antigens, CD↗

PubMed2003

Variations in anatomy at the suprascapular notch possibly causing suprascapular nerve entrapment: an anatomical study.

The purpose of the study was to determine anatomical variations at the suprascapular notch for better understanding of possible predisposing factors for suprascapular nerve entrapment. We dissected 32 shoulders of 16 cadavers between the ages of 39 and 74 years. We observed abnormally oriented superior fibers of the subscapularis muscle in five shoulders of the 16 cadavers, which were covering the entire anterior surface of the suprascapular notch and significantly reducing the available space for the suprascapular nerve. We also detected anterior coracoscapular ligament in six of the 32 shoulders, and calcified superior transverse scapular ligament in four of the shoulders. In this study, we classified the variations for the superior transverse scapular ligament. In conclusion, knowing the anatomical variations in detail along the course of the suprascapular nerve might be important for better understanding of location and source of the entrapment syndrome, especially for individuals who are involved in violent overhead sports activities such as volleyball and baseball. To our knowledge, close relationship of subscapularis muscle with the suprascapular nerve as a possible risk factor for suprascapular nerve entrapment has not been mentioned previously.

Adult↗

PubMed2003

Compression of the suprascapular nerve by a ganglion cyst of the spinoglenoid notch: the arthroscopic solution.

We evaluated an all arthroscopic technique for treating suprascapular nerve entrapment by cyst formation in the spinoglenoid notch. Eight patients showed positive MRI and EMG findings with clinical sign of weakness and pain and with atrophy of the muscle. All patients underwent an all-arthroscopic procedure. The patients were evaluated preoperatively and 6 weeks and 3 months postoperatively and for the latest follow-up by clinical examination, MRI, and EMG. All patients improved in terms of pain, strength, and function. We found six superior labrum anterior and posterior (SLAP) lesions. In these patients the cyst was drained, and the SLAP lesion was repaired. In two patients there was no communication between the joint and the cyst, and therefore capsulotomy was performed and left open. The results of our study show that arthroscopic decompression of the suprascapular nerve can be achieved by an all arthroscopic technique if the cyst formation is located at the spinoglenoid notch.

Adult↗