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At least 847 records · Page 47Linked to original sources
PubMed2004

Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells.

Antigen-presenting cells (APC) tailor immune responses to microbial encounters by stimulating differentiation of CD4 T cells into the Th1 and Th2 lineages. We demonstrate that APC use the Notch pathway to instruct T cell differentiation. Strikingly, of the two Notch ligand families, Delta induces Th1, while Jagged induces the alternate Th2 fate. Expression of these different Notch ligands on APC is induced by Th1- or Th2-promoting stimuli. Th2 differentiation has been considered a default process as APC-derived instructive signals are unknown. We demonstrate that Jagged constitutes an instructive signal for Th2 differentiation, which is independent of IL4/STAT6. Th2 differentiation induced by APC is abrogated in T cells lacking the Notch effector RBPJkappa. Notch directs Th2 differentiation by inducing GATA3 and by directly regulating il4 gene transcription through RBPJkappa sites in a 3' enhancer.

Animals↗
PubMed2002

Characterization of the transcriptional expression of Notch-1 signaling pathway members, Deltex and HES-1, in developing mouse thymocytes.

The Notch transmembrane protein is involved in a broad range of different developmental pathways in vertebrates and invertebrates. Targeted thymocyte expression of the Notch-1 intracellular domain has been shown to affect lineage commitment decisions such as those involving T cell vs. B cell, thymocyte alpha beta vs. gamma delta TCR, as well as CD4 vs. CD8 thymocyte commitment. In this paper, we quantitatively characterize thymocyte RNA expression of two purported transcriptional markers of Notch-1 signaling activity, Deltex and HES-1. Using a semiquantitative RTPCR approach, we show that both Deltex and HES-1 transcriptional levels are developmentally regulated as thymocytes mature from the earliest CD4/CD8 double negative thymocyte stage, through the intermediate CD4/CD8 double positive stage, and finally to the mature CD4 or CD8 single positive stage. Deltex and HES-1, despite both being transcriptional markers of Notch-1 activity, express different patterns of transcriptional activity among the thymocyte subsets. Neither treatment with combined (alpha CD3)/(alpha CD28) antibodies nor the combination of the phorbol ester PMA and calcium ionophore ionomycin affects expression of Deltex in immature thymocytes; however, PMA/ionomycin treatment does downregulate expression of HES-1, an affect mostly mediated by ionomycin. Finally, a difference in HES-1 expression is seen between CD4/CD8 double positive thymocytes isolated from wild-type vs. MHC class I/II deficient mice, suggesting that Notch-1 activity is modulated during in vivo TCR/MHC-ligand selection events.

Animals↗
PubMed1983

Atrial systolic notch on the interventricular septal echogram: an echocardiographic sign of constrictive pericarditis.

Interventricular septal motion during ventricular diastole was analyzed using M-mode echocardiography in 13 patients with constrictive pericarditis and 12 patients with restrictive cardiomyopathy. In seven of eight patients with constrictive pericarditis in sinus rhythm, an abnormal "atrial systolic" notch was observed consisting of abrupt initial posterior motion toward the left ventricle approximately at the middle of the P wave and subsequent anterior motion at the end of the P wave and termination before the R wave. This notch was absent during atrial premature beats that were recorded in two patients. The atrial systolic notch was not observed in any patient with restrictive cardiomyopathy. The septal notch in early ventricular diastole previously described in constrictive pericarditis was seen in 62% of patients with constrictive pericarditis and 25% of patients with restrictive cardiomyopathy. Thus, an abnormal atrial systolic notch may be an additional useful sign to differentiate constrictive pericarditis from restrictive cardiomyopathy. The mechanism may be related to transient late diastolic pressure gradients between both ventricles resulting from asynchrony of left and right atrial contractions.

Diastole↗
PubMed2002

The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis.

We have studied the role of Notch-1 and its antagonist Numb in the activation of satellite cells during postnatal myogenesis. Activation of Notch-1 promoted the proliferation of myogenic precursor cells expressing the premyoblast marker Pax3. Attenuation of Notch signaling by increases in Numb expression led to the commitment of progenitor cells to the myoblast cell fate and the expression of myogenic regulatory factors, desmin, and Pax7. In many intermediate progenitor cells, Numb was localized asymmetrically in actively dividing cells, suggesting an asymmetric cell division and divergent cell fates of daughter cells. The results indicate that satellite cell activation results in a heterogeneous population of precursor cells with respect to Notch-1 activity and that the balance between Notch-1 and Numb controls cellular homeostasis and cell fate determination.

Animals↗
PubMed2005

Acoustic rhinometry: anatomic correlation of the first two notches found in the nasal echogram.

UNLABELLED: The graphic obtained by acoustic rhinometry in Caucasian adult individuals with no nasal affections clearly shows two notches at the beginning of the nasal echogram. However, there are controversies in the literature concerning their anatomic correlation. AIM: The aim of this study was to obtain data that would contribute to the anatomic correlation of these two notches. STUDY DESIGN: Clinical prospective. MATERIAL AND METHOD: We analyzed the nasal echogram of 35 volunteers in basal conditions, after decongestion and after obstruction of the nasal valve by using cotton impregnated with Vaseline. RESULTS: We identified statistically significant reduction and increase of the cross-sectional area only for the second notch after obstruction of the nasal valve and after decongestion, respectively. CONCLUSION: The analysis of the results suggested that the first notch of the nasal echogram refers to the nostril and the second notch refers to the nasal valve as a whole.

Adolescent↗
PubMedDate not supplied

Transposon-dependent mutant phenotypes at the Notch locus of Drosophila.

Many mutations at complex genetic loci in the fruitfly Drosophila melanogaster are associated with insertions of transposable elements. At the Notch locus, members of one class of insertion-associated mutations, termed glossy-like, produce a recessive viable, smooth-eye phenotype with mottled pigmentation. Members of a second class, facet, produce a recessive viable, rough-eye phenotype with homogeneous pigmentation. Both classes of mutations fail to complement Notch lethal mutations, so they behave as Notch alleles. Here we report that each glossy-like mutation is associated with an insertion of the same transposable element (flea). Each flea insertion occurs in the same orientation, but at different locations within intervening sequences of the Notch locus. In contrast, each facet mutation is associated with insertion of a unique, non-flea, transposable element. Insertions producing a facet phenotype and insertions causing a glossy-like phenotype can break Notch intervening sequences at precisely the same location. This suggests that the type of insertion element rather than its position within an affected gene is the primary determinant of the phenotype observed.

Animals↗
PubMed2004

Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling.

Although the Notch and JAK-STAT signalling pathways fulfill overlapping roles in growth and differentiation regulation, no coordination mechanism has been proposed to explain their relationship. Here we show that STAT3 is activated in the presence of active Notch, as well as the Notch effectors Hes1 and Hes5. Hes proteins associate with JAK2 and STAT3, and facilitate complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. Furthermore, suppression of endogenous Hes1 expression reduces growth factor induction of STAT3 phosphorylation. STAT3 seems to be essential for maintenance of radial glial cells and differentiation of astrocytes by Notch in the developing central nervous system. These results suggest that direct protein-protein interactions coordinate cross-talk between the Notch-Hes and JAK-STAT pathways.

Animals↗
PubMed2005

Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism.

Notch signals are necessary for the functional outcomes of T cell receptor beta-selection, including differentiation, proliferation and rescue from apoptosis. The mechanism underlying this requirement for T cell development is unknown. Here we show that Notch receptor and Delta-like 1 ligand interactions promoted the survival of CD4(-)CD8(-) pre-T cells through the maintenance of cell size, glucose uptake and metabolism. Furthermore, the trophic effects of Notch signaling were mediated by the pathway of phosphatidylinositol-3-OH kinase and the kinase Akt, such that expression of active Atk overcame the requirement for Notch in beta-selection. Collectively, our results demonstrate involvement of Notch receptor-ligand interactions in the regulation of cellular metabolism, thus enabling the autonomous signaling capacity of the pre-T cell receptor complex.

Animals↗
PubMed2005

Notch signaling in the mammalian central nervous system: insights from mouse mutants.

The Notch pathway, although originally identified in fruit flies, is now among the most heavily studied in mammalian biology. In mice, loss-of-function and gain-of-function work has demonstrated that Notch signaling is essential both during development and in the adult in a multitude of tissues. Prominent among these is the CNS, where Notch has been implicated in processes ranging from neural stem cell regulation to learning and memory. Here we review the role of Notch in the mammalian CNS by focusing specifically on mutations generated in mice. These mutations have provided critical insight into Notch function in the CNS and have led to the identification of promising new directions that are likely to generate important discoveries in the future.

Animals↗
PubMed2005

High-resolution crystal structure of the human Notch 1 ankyrin domain.

The Notch receptor is part of a highly conserved signalling system of central importance to animal development. Its ANK (ankyrin) domain is required for Notch-mediated signal transduction. The crystal structure of the human Notch 1 ANK domain was solved by molecular replacement at 1.9 A (1 A=0.1 nm) resolution, and it shows that the features identified in the Drosophila homologue are conserved. The domain has six of the seven ANK repeats predicted from sequence. The putative first repeat, which has only part of the consensus and a long insertion, is disordered in both molecules in the asymmetric unit, possibly due to the absence of the RAM (RBPJkappa-associated molecule) region N-terminal to it. The exposed hydrophobic core is involved in intermolecular interactions in the crystal. Evolutionary trace analysis identified several residues that map to the hairpins of the structure and may be of functional importance. Based on the Notch 1 ANK structure and analysis of homologous Notch ANK sequences, we predict two possible binding sites on the domain: one on the concave surface of repeat 2 and the other below the hairpins of repeats 6-7.

Amino Acid Sequence↗
PubMed1999

Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.

The Notch family of proteins consists of transmembrane receptors that play a critical role in the determination of cell fate. Genetic studies in Caenorhabditis elegans suggest that the presenilin proteins, which are associated with familial Alzheimer's disease, regulate Notch signaling. Here we show that proteolytic release of the Notch-1 intracellular domain (NICD), an essential step in the activation of Notch signaling, is markedly reduced in presenilin-1 (PS1)-deficient cells and is restored by PS1 expression. Nuclear translocation of the NICD is also markedly reduced in PS1-deficient cells, resulting in reduced transcriptional activation. Mutations in PS1 that are associated with familial Alzheimer's disease impair the ability of PS1 to induce proteolytic release of the NICD and nuclear translocation of the cleaved protein. These results suggest that PS1 plays a central role in the proteolytic activation of the Notch-1-signaling pathway and that this function is impaired by pathogenic PS1 mutations. Thus, dysregulation of proteolytic function may underlie the mechanism by which presenilin mutations cause Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.

Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling intermediates of Notch1 and suggest that the role of proteolysis in Notch signaling has been conserved. Here we demonstrate that extracellularly truncated Notch homologs are substrates for a presenilin-dependent gamma-secretase activity. Despite minimal conservation within the transmembrane domain, the requirement for a specific amino acid (P1' valine) and its position at the cleavage site relative to the cytosolic border of the transmembrane domain are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional regulatory protein CSL. All four Notch proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized gamma-secretase substrates from two to five. Despite a high degree of structural homology and the presenilin-dependent activity of truncated Notch proteins, the extent that this reflects functional redundancy is unknown.

Amino Acid Sequence↗
PubMed2003

Evidence that C promoter-binding factor 1 binding is required for Notch-1-mediated repression of activator protein-1.

Cell fate determination in invertebrate and vertebrate systems is regulated by the Notch signaling pathway. Four mammalian Notch genes, Notch 1-4, encode differentially expressed transmembrane receptors. The canonical Notch pathway involves proteolytic liberation of the Notch-1 intracellular domain (NIC-1), which activates CSL (CBF1, Su(H), and Lag-1)-mediated transactivation. We showed previously that NIC-1 also represses activator protein-1 (AP-1)-mediated transactivation. The N-terminal RAM (RBP-Jkappa associated molecule) domain of NIC-1 was required for both activation and repression. To investigate the mechanism of AP-1 repression, we tested whether distinct sequences within the RAM domain mediate activation versus repression. We analyzed the capacity of RAM domain mutants to bind endogenous CBF1, to activate CSL-mediated transactivation, and to repress AP-1. A mutant lacking 20 amino acids of the RAM domain (Delta1759-1778) resembled the RAM domain deletion mutant in being defective in all activities. Analysis of 14 deletion and alanine substitution mutants revealed a correlation between CBF1 binding, CSL-mediated transactivation, and AP-1 repression. Stably transfected K562 cells could only tolerate very low level expression of wild-type NIC-1 and NIC-1 mutants retaining activation/repression activities. By contrast, transcriptionally compromised NIC-1 mutants accumulated at high levels. These results support a model in which the binding of NIC-1 to CBF1 is required for AP-1 repression and reveal a powerful cell-sensing mechanism that suppresses the levels of transcriptionally competent NIC-1.

Alanine↗
PubMed1989

Phenotypic and molecular analysis of the facets, a group of intronic mutations at the Notch locus of Drosophila melanogaster which affect postembryonic development.

The function of the Notch locus of Drosophila melanogaster is essential for normal development both during embryogenesis and during postembryonic stages. In the embryo its function is necessary for the correct segregation of neural from epidermal lineages. During postembryonic stages Notch exhibits pleiotropic effects that are both tissue- and stage-specific. Here, we examine a group of six recessive mutations, the facets (fa, fa3, fag, fag-2, fafx and fasw), which affect eye morphology and have been previously shown to be associated with the insertion of transposable elements in an intronic region of Notch. The analysis of revertants has shown that the mutant phenotype depends on the presence of the transposable element and that the disruption of the wild-type sequence organization per se is not its cause. Four of these alleles, even though they are associated with the insertion of the same transposable element, display considerably different phenotypes. Therefore, no simple correlation exists between the mutant phenotype and the type of inserted element. A comparison of the tissue localization of the Notch and the transposable element transcripts revealed that in the third larval instar the elements are transcribed in both orientations in tissues in which Notch is also transcriptionally active. The complexity of the defects associated with the facet alleles, as well as the findings of the transcriptional analysis, indicate that a mutational mechanism based solely on transcriptional interference is not sufficient to explain the nature of the mutational event. It is likely that in these mutations alterations, in the temporal and/or spatial context caused by transcriptional and perhaps posttranscriptional interference mechanisms by the inserted elements, may be responsible for the mutant phenotype.

Alleles↗
PubMed1977

The cytogenetics of a recessive visible mutant associated with a deficiency adjacent to the notch locus in Drosophila melanogaster.

The recessive visible faswb allele in Drosophila is an interband deletion between salivary band 3C5, 6 and 7. Heterozygosity for the deletion does not suppress recombination between faswb and mutant sites at Notch adjacent to it.--Df(1)w67k30, deficient for salivary bands 3C2 to 6, is the left of faswb. By crossing over within the homologous bit of interband retained in w67k30 and faswb, the two deficiencies can be linked. Cytologically, 3C7, "fused" to 3C5,6 in faswb, becomes "fused" to 3C1 when the two are coupled. In the double deletion, the recessive visible phenotype of the faswb "allele* is suppressed. Both w67k30 and faswb can be recovered by uncoupling the two deficiencies.--The data suggest that the mutant faswb does not represent a lesion at Notch; the entire gene or locus seems to be present. The interband deletion in faswb has secondarily moved an intact Notch locus to a foreign environment that interferes with its normal function. When faswb is linked to w67k30, the interference is eliminated and normal Notch functions resume.--The position of Notch on the salivary gland chromosome is reviewed in relation to the information obtained in these experiments.

Animals↗
PubMed1999

Femoral intercondylar notch measurements in osteoarthritic knees.

METHODS: We measured the dimensions of the intercondylar notch of the femur in 32 patients with primary severe osteoarthrosis (OA) of the knee and 54 embalmed cadaveric knees. RESULTS: There were 56 knees with morphologically normal anterior cruciate ligament (ACL), 11 knees with lax or partially ruptured ACL and 19 knees with missing ACL. The average width of the intercondylar notch in knees with lax and missing ACL was significantly narrower than that of knees with normal ACL. In addition, knees with missing ACL had a significantly smaller notch depth than knees with normal ACL. In medial compartment OA (56 knees), the notch width and depth in knees with severe OA (37 knees) were significantly smaller than those in normal (19 knees) and mild to moderate OA groups (19 knees). CONCLUSION: Our results indicate that osteophyte growth in the femoral intercondylar notch seems to correlate with the progression of medial compartment OA of the knee.

Aged↗
PubMed2005

Notched delta, phenotype, and Angelman syndrome.

The notched delta pattern is one of the characteristic EEG features found in Angelman syndrome patients. The purpose of this study was to evaluate the possibility of using the notched delta pattern as a detection tool for Angelman syndrome patients by analyzing its frequency in a tertiary care pediatric center, its specificity for Angelman syndrome, and the age at which it was observed. The authors performed a retrospective review of the video-EEG recordings of all the patients who had either the notched delta pattern or a phenotype consistent with Angelman syndrome. The notched delta was observed in 1.1% of all the EEGs performed. Its specificity for Angelman syndrome was evaluated at 38%. The youngest age at which it was noted was 14 months. The results indicate that the notched delta pattern is relatively rare, but more frequent than expected, and is easily recognizable. The pattern was observed not only in Angelman syndrome patients, but also in children with a spectrum of conditions wider than reported. It is a powerful detection tool for Angelman syndrome when correlated to a suggestive phenotype, and the association of these features should raise suspicion for Angelman syndrome in both infants and adults.

Adolescent↗
PubMed1997

Acetabular notch.

Ultrasound images of dysplastic and/or unstable hips often display an indentation or notch at the superolateral part of the acetabulum where the iliac wing joins the acetabular roof. We reviewed the ultrasound and subsequent radiographic examinations of 295 babies examined in our hip screening clinic. Of the hips with a notch demonstrable at the first ultrasound, 97% had a persistent notch at the second ultrasound and in 79% the notch was apparent on the 3-month radiograph. When the notch persists, we believe that it represents damage to the lateral acetabular ring epiphysis and delayed maturation of the lateral acetabulum.

Acetabulum↗