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PubMed2005

Notch in vertebrates--molecular aspects of the signal.

Notch is a receptor consisting of a single path transmembrane protein which is essential for stem cell regulation in both vertebrates and invertebrates. We have investigated the function of Notch signaling and found that ligands of the Notch receptor (Delta and Serrate) sometimes act as receptor modulators in a cell autonomous manner; the balance of their activity as ligands explains satisfactorily 'lateral inhibition' as well as 'lateral specification'. This model explains not only fly morphogenesis, but also the general regulation of stem cells. In vertebrates, members of a novel family of genes which encode small secretory proteins, CCN, were demonstrated to bind to Notch and stimulate signaling. This is not a ligand type binding, but rather a modifier of the protein structure of Notch, so as to form a macromolecular complex. This association may open up novel perspectives on Notch signaling, for instance in the movement of cells involved in somite segmentation or angiogenesis. Thus, a well-conserved signal such as Notch seems to have changed in function during the evolution of vertebrates.

Animals↗
PubMed2006

Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.

Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.

Alleles↗
PubMed2006

Notch signaling induces apoptosis in primary human CD34+ hematopoietic progenitor cells.

Notch signaling regulates diverse cell fate decisions during development and is reported to promote murine hematopoietic stem cell (HSC) self-renewal. The purpose of this study was to define the functional consequences of activating the Notch signaling pathway on self-renewal in human HSCs. Subsets of human umbilical cord blood CD34(+) cells were retrovirally transduced with the constitutively active human Notch 1 intracellular domain (N1ICD). N1ICD-transduced cells proliferated to a lesser extent in vitro than cells transduced with vector alone, and this was accompanied by a reduction in the percentage and absolute number of CD34(+) cell populations, including CD34(+)Thy(+)Lin(-) HSCs. Ectopic N1ICD expression inhibited cell cycle kinetics concurrent with an upregulation of p21 mRNA expression and induced apoptosis. Transduction of cells with HES-1, a known transcriptional target of Notch signaling and a mediator of Notch function, had no effect on HSC proliferation, indicating that the mechanism of the Notch-induced effect is HES-1-independent. The results of this study show that activation of the Notch signaling pathway has an inhibitory effect on the proliferation and survival of human hematopoietic CD34(+) cells populations. These findings have important implications for strategies aimed at promoting self-renewal of human HSCs.

Antigens, CD34↗
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↗
PubMed2003

Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors.

Interactions between T cell precursors and thymic stromal cells are essential during thymocyte development. However, the role of the thymus in initial commitment of lymphoid progenitors to the T lineage remains controversial, with data providing evidence for both extra- and intrathymic commitment mechanisms. In this context, it is clear that Notch1 is an important mediator during initiation of T cell development. Here we have analyzed the mechanisms regulating Notch activation in lymphoid precursors at extrathymic sites and in the thymus, including stages representing the first wave of embryonic thymus colonization on embryonic day 12 of gestation. We show that Notch activation in migrant lymphoid precursors requires entry into the thymic microenvironment where they are exposed to Notch ligands expressed by immature thymic epithelial cells. Moreover, continued Notch signaling in such precursors requires sustained interactions with Notch ligands. Collectively, these findings suggest a role for Notch in an intrathymic mechanism of T cell lineage commitment involving sustained interactions with Notch ligand bearing thymic epithelium.

Animals↗
PubMed2006

Small interfering RNA-mediated knockdown of notch ligands in primary CD4+ T cells and dendritic cells enhances cytokine production.

The key interaction in the adaptive immune system's response to pathogenic challenge occurs at the interface between APCs and T cells. Families of costimulatory and coinhibitory molecules function in association with the cytokine microenvironment to orchestrate appropriate T cell activation programs. Recent data have demonstrated that the Notch receptor and its ligands also function at the APC:T interface. In this study, we describe synthetic small interfering RNA (siRNA) sequences targeting the human Notch ligands Delta1, Jagged1 and Jagged2. Transfection of these siRNAs into human primary CD4(+) T cells and monocyte-derived dendritic cells leads to knockdown of endogenous Notch ligand message. Knockdown of any one of these three Notch ligands in dendritic cells enhanced IFN-gamma production from allogeneic CD4(+) T cells in MLR. In contrast, Delta1 knockdown in CD4(+) T cells selectively enhanced production of IFN-gamma, IL-2, and IL-5 in response to polyclonal stimulation, while Jagged1 or Jagged2 knockdown had no effect. Strikingly, blockade of Notch cleavage with a gamma secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism. These data show for the first time that the Notch pathway can be targeted by siRNA, and that its antagonism may be a unique therapeutic opportunity for immune enhancement.

Animals↗
PubMed2006

Notch and minichromosome maintenance (MCM) proteins: integration of two ancestral pathways in cell cycle control.

Notch transmembrane receptors govern a highly evolutionarily conserved intercellular signaling mechanism activated by the engagement of Notch receptors by their cognate ligands expressed on neighboring cells. The subsequently cleaved intracellular domain of Notch receptors translocates to the nucleus where it interacts with the transcriptional regulator CSL, thereby regulating expression of target genes. The Notch pathway controls cell fate by regulating proliferation, differentiation, and apoptosis. Mini-chromosome maintenance (MCM) proteins are components of the prereplicative complex (pre-RC) that are essential for DNA replication. It has recently been shown that activated Notch downregulates mini-chromosome-maintenance (MCM) proteins MCM2 and MCM6 by a CSL-dependent mechanism. Here, we review the canonical pathway mediated by Notch receptors and discuss recent findings connecting the Notch pathway with the ancestral MCM complex during cell cycle progression.

Animals↗
PubMed1999

Drosophila presenilin is required for neuronal differentiation and affects notch subcellular localization and signaling.

Presenilins are a highly conserved family of proteins first identified as causative genes in early onset familial Alzheimer's disease. Recent studies have suggested a role for presenilins in the Notch-signaling pathway, but their specific function within this pathway remains unclear. Here, we have characterized the Drosophila presenilin gene and protein and studied their interaction with Notch in both mutants and transgenics. We find that the Drosophila presenilin protein is proteolytically cleaved and broadly expressed during development with the highest levels in neurons within the larval CNS. We also show that mutations in Drosophila presenilin (Dps) genetically interact with Notch and result in an early pupal-lethal phenotype characterized by defects in eye and wing development and incomplete neuronal differentiation within the larval CNS. Moreover, we find that processing of Notch in the Golgi by the furin protease is unaffected in Dps mutants and that Notch is present and may even accumulate on the plasma membrane of neuroblasts in the larval CNS of Dps mutants. In contrast, overexpression of Dps in transgenics causes Notch to accumulate in the cytoplasm. Taken together, these results indicate that Drosophila presenilin is required for proper neuronal differentiation and may regulate the subcellular localization of Notch proteins within cells, necessary for their accumulation and subsequent signaling capabilities.

Animals↗
PubMed2006

Notch signal transduction induces a novel profile of Kaposi's sarcoma-associated herpesvirus gene expression.

Kaposi's sarcoma-associated herpesvirus (KSHV) RTA transcription factor is recruited to its responsive elements through interaction with RBP-Jkappa that is a downstream transcription factor of the Notch signaling pathway that is important in development and cell fate determination. This suggests that KSHV RTA mimics cellular Notch signal transduction to activate viral lytic gene expression. Here, I demonstrated that unlike other B lymphoma cells, KSHV-infected primary effusion lymphoma BCBL1 cells displayed the constitutive activation of ligand-mediated Notch signal transduction, evidenced by the Jagged ligand expression and the complete proteolytic process of Notch receptor I. In order to investigate the effect of Notch signal transduction on KSHV gene expression, human Notch intracellular (hNIC) domain that constitutively activates RBP-Jkappa transcription factor activity was expressed in BCBL1 cells, TRExBCBL1-hNIC, in a tetracycline inducible manner. Gene expression profiling showed that like RTA, hNIC robustly induced expression of a number of viral genes including K5 immune modulatory gene resulting in downregulation of MHC I and CD54 surface expression. Finally, the genetic analysis of KSHV genome demonstrated that the hNIC-mediated expression of K5 during viral latency consequently conferred the downregulation of MHC I and CD54 surface expression. These results indicate that cellular Notch signal transduction provides a novel expression profiling of KSHV immune deregulatory gene that consequently confers the escape of host immune surveillance during viral latency.

Antigens, Surface↗
PubMed1996

Sex differences in the sciatic notch of great apes and modern humans.

The sciatic notch has been widely used as a sexing criterion in modern humans. In order to better understand the sex differences of this feature in modern humans and great apes, four measurements of the sciatic notch were taken on samples of modern humans and great apes of known sex. Univariate (ANOVA) analysis and discriminant function analysis were performed on the extant taxa to determine: (1) the discriminating power of each variable in these samples of known group membership; and (2) which of these extant taxa shows the best discrimination between the sexes for the sciatic notch. Of the four extant taxa, the sciatic notch of Homo sapiens is the most sexually dimorphic, followed by Gorilla gorilla, and more weakly by Pongo pygmaeus, while Pan troglodytes is the least dimorphic of these taxa. Since the presence of a well defined sciatic notch is a hominid trait resulting from the dorsal extension of the posterior ilium, the close approximation of the sacrum to the acetabulum, the shortened ischium, and the accentuation of the ischial spine as part of the bipedal adaptation, it seems likely that the configuration of the sciatic notch in hominids was initially related to bipedalism, not reproduction. The development of sex differences in the sciatic notch of modern humans is more likely to have occurred after the transition to bipedality.

Analysis of Variance↗
PubMed1995

Statistical study of sexual dimorphism in the human fetal sciatic notch.

Whether human fetal skeletal remains exhibit sexual dimorphism has been the subject of considerable debate. Most attention in this debate has focused on the greater sciatic notch of the ilium, since it is a gross morphological characteristic with known sex differences in the adult and is easily seen in fetal skeletal remains. Unfortunately, previous traditional morphometric analyses of the fetal sciatic notch have led to ambiguous results. The purpose of this study is to determine whether differences between the sexes can be discerned when modern morphometric techniques are applied to the fetal sciatic notch. Photographs of the ventral side of 133 fetal ilia of known age and sex from the Trotter Collection of Washington University were digitized, and the trace coordinates used for all subsequent analyses. The results of the analysis demonstrate that there is significant sexual dimorphism in the anterior to posterior location of the maximum depth of the sciatic notch, but that the depth of the notch itself is not dimorphic. While there is significant sexual dimorphism in the shape of the sciatic notch, the amount of overlap between males and females is too great for the sciatic notch to be used as a reliable indicator of sex.

Anthropology, Physical↗
PubMed1990

Value of notching and slurring of the resting QRS complex in the detection of ischemic heart disease.

The resting 12-lead ECG has long been known to be an insensitive marker of underlying ischemic heart disease (IHD). The purpose of this study was to determine if QRS complex notching and slurring is of significant value as a diagnostic discriminator in the detection of IHD. The data from 205 consecutive patients coming to cardiac catheterization for evaluation of probable IHD were initially analyzed. Eighty-three patients were excluded based upon ventricular hypertrophy, bundle-branch block, lack of data, and pacemaker rhythm. The balance, 122 patients (mean age 61.7 years), were evaluated for angiographic evidence of IHD, ECG findings of QRS notching or slurring, and abnormal Q waves. The data revealed a high prevalence of QRS notching or slurring; 62.2% in those patients with IHD, double the prevalence of significant Q waves (33.3%). The two markers had an approximately equal prevalence (QRS notching or slurring 61.7% vs. Q waves 53.2%) in patients with angiographic evidence of infarction; however, in patients with less than infarct criteria for IHD, the prevalence of QRS notching or slurring was 62.8%, while only 11.6% showed abnormal Q waves. Analysis indicated that QRS notching or slurring has a sensitivity of 62.2% and a specificity of 93.8% for the detection of IHD. The study demonstrates that QRS notching or slurring is a moderately sensitive and a very specific marker of ischemic heart disease in selected patients when using the resting ECG, and is of greatest value in those patients with lesser degrees of ischemic myocardial injury where the prevalence of Q waves is low.

Coronary Disease↗
PubMed2005

Eosinophilic differentiation is promoted by blockage of Notch signaling with a gamma-secretase inhibitor.

Although increasing evidence supports the inhibitory role of Notch in granulocyte differentiation, the direct effects of Notch on the differentiation and maturation of eosinophils, one type of granulocyte, have not yet been studied. We investigated whether a blockage of Notch signaling promoted the differentiation of eosinophils from umbilical cord blood (UCB) cells. Freshly isolated UCB cells were cultured with IL-3, IL-5 and GM-CSF in the presence or absence of a gamma-secretase inhibitor L-685,458, and examined for the expression of major basic protein (MBP). Freshly isolated UCB cells expressed mRNA and proteins for Notch 1, Notch 2, Delta 1, and Jagged 1. MBP expression in cultures with the inhibitor was significantly increased, as compared with the cultures in the absence of the inhibitor. Treatment with the inhibitor was accompanied by a decrease in Hes 1 mRNA expression, indicative of Notch-mediated signaling for the inhibitor effect. UCB cells cultured with the inhibitor for 28 days displayed similar levels of CCR3, a late marker of eosinophil development, as compared with the cells cultured without the inhibitor, but almost completely lost chemotaxis response to eotaxin. Our data suggest that Notch signaling may modulate eosinophil migration at the mature stage as well as inhibit eosinophil differentiation.

Amyloid Precursor Protein Secretases↗
PubMed2006

Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms.

Aspartyl-(asparagyl)-beta-hydroxylase (AAH) is overexpressed in various malignant neoplasms, including hepatocellular carcinomas (HCCs). The upstream regulation of AAH and its functional role in Notch-mediated signaling and motility in HCC cells was accessed. The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin-like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC-free human liver biopsy specimens using real-time quantitative RT-PCR and Western blot analysis. Overexpression of AAH was detected in 87% of the HCC relative to the paired HCC-free liver tissue. IRS-1, IRS-2, and IRS-4 were each overexpressed in 80% of the HCC samples, and IGF-I and IGF-2 receptors were overexpressed in 40% and 100% of the HCCs, respectively. All HCC samples had relatively increased levels of Notch-1 and HES-1 gene expression. Overexpression of AAH led to increased levels of Notch, and co-immunoprecipitation experiments demonstrated a direct interaction between AAH and Notch as well as its ligand Jagged. In conclusion, contributions to the malignant phenotype of HCC is due to activation of IGF-I and IGF-II signaling that results in over-expression of both AAH and Notch. The functional role of AAH in relation to cell motility has been linked to increased activation of the Notch signaling pathway.

Aged↗
PubMed2003

Right posterior hepatic notch sign: a simple diagnostic MR finding of cirrhosis.

PURPOSE: To determine the frequency of occurrence of the right posterior hepatic notch sign at MR imaging in patients with cirrhosis, and to assess its diagnostic capability of this sign as a simple diagnostic MR finding of cirrhosis. MATERIALS AND METHODS: This study population included 330 patients with pathologically proved cirrhosis (N = 202) or without clinical evidence of chronic liver diseases (N = 128, control group). MR images were qualitatively evaluated for the presence of the right posterior hepatic notch sign. This sign was considered present if there was a sharp notch in the right posterior surface of the liver. The presence of the expanded gallbladder fossa sign was also evaluated during the same reading session. RESULTS: The right posterior hepatic notch sign was observed in 145 of the 202 patients in the cirrhosis group, while this sign was seen in only two of the 128 patients in the control group (P < 0.0001). The sensitivity, specificity, and accuracy of this sign for the MR diagnosis of cirrhosis were 72%, 98%, and 82%, respectively. When the presence of either the expanded gallbladder fossa sign or the right posterior hepatic notch sign was considered for the MR diagnosis of cirrhosis, the sensitivity and accuracy increased to 86% and 89%, respectively. CONCLUSION: The right posterior hepatic notch sign can be used as a simple and highly specific sign of cirrhosis, if present. The diagnostic performance can be improved when the presence of either the expanded gallbladder fossa sign or the right posterior hepatic notch sign was considered.

Case-Control Studies↗
PubMed1999

Engineered truncations in the Drosophila mastermind protein disrupt Notch pathway function.

The phenotypes and genetic interactions associated with mutations in the Drosophila mastermind (mam) gene have implicated it as a component of the Notch signaling pathway. However, its function and site of action within many tissues requiring Notch signaling have not been thoroughly investigated. To address these questions, we have constructed truncated versions of the Mam protein that elicit dominant phenotypes when expressed in imaginal tissues under GAL4-UAS regulation. By several criteria, these effects appear to phenocopy loss of function for the Notch pathway. When expressed in the notum, truncated Mam results in failure of lateral inhibition within proneural clusters and perturbations in cell fate specification within the sensory organ precursor cell lineage. Expression in the wing is associated with vein thickening and margin defects, including nicking and bristle loss. The truncation-associated wing margin phenotypes are modified by mutations in Notch and Wg pathway genes and are correlated with depressed expression of wg, cut, and vg. These data support the idea that Mam truncations have lost key effector domains and therefore behave as dominant-negative proteins. Coexpression of Delta or an activated form of Notch suppresses the effects of the Mam truncation, suggesting that Mam can function upstream of ligand-receptor interaction in the Notch pathway. This system should prove useful for the investigation of the role of Mam within the Notch pathway.

Animals↗
PubMed1993

Motch A and motch B--two mouse Notch homologues coexpressed in a wide variety of tissues.

Notch is one of the neurogenic genes of Drosophila controlling the decision between ectodermal and neural fate for cells in the early embryo. We have used a polymerase chain reaction (PCR)-based strategy to identify cDNA clones representing two mouse homologues to the Drosophila Notch gene. One of the genes, Motch A, is the mouse orthologue to the previously cloned Notch genes in Xenopus, rat, and man. The other gene, Motch B, is more distantly related to the characterized vertebrate Notch genes, but of equal homology to the Drosophila Notch as is Motch A, and therefore represents a distinct branch of a vertebrate Notch gene family. The Motch A and Motch B branches probably arose by gene duplication early in vertebrate evolution. Both Motch A and Motch B retain the same principal structure, encode mRNAs of approximately 10 kilobases, are expressed during mouse embryogenesis, and have largely overlapping expression patterns in adult tissues. We discuss possible consequences of expressing two closely related Notch homologues in the same set of tissues in terms of cell-cell signaling and differentiation control.

Amino Acid Sequence↗
PubMed1989

Frequency content of the QRS notching in high-fidelity canine ECG.

High-fidelity ECGs, defined as ECG signals including high-frequency components, have been studied and variations in the incidence of fine notches and slurs on the QRS complex were reported in different myocardial pathologies. These observations might be of clinical importance since they suggested a noninvasive marker for cardiac dysfunctions. We studied high-fidelity ECG waveforms displaying pronounced notches and slurs. Signals were obtained from 12 anesthetized dogs. Computer analysis included digital averaging, followed by digital filtering in different frequency bands in order to determine the frequency range corresponding to notches and slurs. Low-pass filtering of the low-noise average waveforms was performed while gradually lowering the upper frequency limit, until the fine notch (or slur) could no longer be visually detected, thus determining the lower limit of its frequency content. A band cutoff filter was then applied to the original average waveform. The lower limit of the band cutoff filter was set at the frequency previously determined as the lower limit of the notch (or slur), and its upper limit was determined by gradual raising until the notch (or slur) was visually indistinct. Following this approach, the notches were found to contribute to a frequency range of 40-185 Hz, whereas the slurs contributed only to the lower subrange of this frequency band below 100 Hz.

Animals↗