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PubMed1985

The molecular genetics of the Notch locus in Drosophila melanogaster.

The Notch locus of Drosophila melanogaster profoundly affects differentiation of the central nervous system in the early embryo. Previous molecular studies suggested that the locus spans 40 kb of DNA and encodes a 10.5-kb poly(A)+ RNA. The results of genetic, cytogenetic, and molecular studies of newly induced and preexisting Notch alleles are reported. Molecular analysis of 5' flanking mutations defines a distal limit for the locus, and transcriptional activity of Notch in relation to that of flanking transcription units provides evidence regarding the proximal limit. Examination of a set of mutable alleles implicates a foldback transposable element as the basis of chromosomal instability, and shows that insertion sequences within the locus do not necessarily result in a mutant phenotype. The results are discussed with regard to existing developmental and genetic analyses, and a molecular model is proposed that attempts to explain the pleiotropic action of Notch.

Alleles↗
PubMed1993

A deep lateral femoral notch as a sign of acutely torn anterior cruciate ligament.

Anterior cruciate ligament (ACL) tears are frequently associated with abnormalities of the lateral femoral condyle as shown by magnetic resonance imaging. The mechanism of injury has been described as due to bone compression during knee trauma. This may lead to compression of the lateral condylopatellar notch (sulcus). It has been suggested that detection of a deep notch on the plain lateral radiograph is a useful indirect sign of ACL tear. Depth of this notch was measured in 34 consecutive prospective patients assessed as having acute ACL tear clinically and proven at arthroscopy. In no patient was the notch deep, suggesting that this is not a useful sign in acute tears of the anterior cruciate ligament.

Acute Disease↗
PubMed2005

Automatic intraaortic balloon pump timing using an intrabeat dicrotic notch prediction algorithm.

PURPOSE: The efficacy of intraaortic balloon counterpulsation (IABP) during arrhythmic episodes is questionable. A novel algorithm for intrabeat prediction of the dicrotic notch was used for real time IABP inflation timing control. DESCRIPTION: A windkessel model algorithm was used to calculate real-time aortic flow from aortic pressure. The dicrotic notch was predicted using a percentage of calculated peak flow. Automatic inflation timing was set at intrabeat predicted dicrotic notch and was combined with automatic IAB deflation. EVALUATION: Prophylactic IABP was applied in 27 patients with low ejection fraction (< 35%) undergoing cardiac surgery. Analysis of IABP at a 1:4 ratio revealed that IAB inflation occurred at a mean of 0.6 +/- 5 ms from the dicrotic notch. In all patients accurate automatic timing at a 1:1 assist ratio was performed. Seventeen patients had episodes of severe arrhythmia, the novel IABP inflation algorithm accurately assisted 318 of 320 arrhythmic beats at a 1:1 ratio. CONCLUSIONS: The novel real-time intrabeat IABP inflation timing algorithm performed accurately in all patients during both regular rhythms and severe arrhythmia, allowing fully automatic intrabeat IABP timing.

Aged↗
PubMed2006

Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.

Notch receptors transduce essential developmental signals between neighboring cells by forming a complex that leads to transcription of target genes upon activation. We report here the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1 (ANK), the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). Together, CSL and ANK create a groove to bind the MAML-1 polypeptide as a kinked, 70 A helix. The composite binding surface likely restricts the recruitment of MAML proteins to promoters on which Notch:CSL complexes have been preassembled, ensuring tight transcriptional control of Notch target genes.

Amino Acid Sequence↗
PubMed2005

The intracellular domain of Notch ligand Delta1 induces cell growth arrest.

Notch signaling involves proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands, Delta or Jagged; and the resultant soluble intracellular domain of Notch stimulates a cascade of transcriptional events. The Delta1 ligand also undergoes proteolytic cleavage upon Notch binding, resulting in the production of a free intracellular domain. We demonstrate that the expression of the intracellular domain of Delta1 results in a non-proliferating senescent-like cell phenotype which is dependent on the expression of the cell cycle inhibitor, p21, and is abolished by co-expression of constitutively active Notch1. These data suggest a new intracellular role for Delta1.

Animals↗
PubMed2005

Mind bomb1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling.

The Notch-Delta signaling pathway controls many conserved cell determination events. While the Notch end is fairly well characterized, the Delta end remains poorly understood. Mind bomb1 (MIB1) is one of two E3 ligases known to ubiquitinate Delta. We report here that a targeted mutation of Mib1 in mice results in embryonic lethality by E10.5. Mutants exhibit multiple defects due to their inability to modulate Notch signaling. As histopathology revealed a strong neurogenic phenotype, this study concentrates on characterizing the Mib1 mutant by analyzing Notch pathway components in embryonic neuroepithelium prior to developmental arrest. Premature neurons were observed to undergo apoptosis soon after differentiation. Aberrant neurogenesis is a direct consequence of lowered Hes1 and Hes5 expression resulting from the inability to generate Notch1 intracellular domain (NICD1). We conclude that MIB1 activity is required for S3 cleavage of the Notch1 receptor. These results have direct implications for manipulating the differentiation of neuronal stem cells and provide a putative target for the modulation of specific tumors.

Amino Acid Sequence↗
PubMed2003

FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development.

FGF10 plays an important role in the morphogenesis of several tissues by control of mesenchymal-to-epithelial signaling. In the pancreas, mesenchymal FGF10 is required to maintain the Pdx1-expressing epithelial progenitor cell population, and in the absence of FGF10 signaling, these cells fail to proliferate. Ectopic expression of FGF10 in the pancreatic epithelium caused increased proliferation of pancreatic progenitor cells and abrogation of pancreatic cell differentiation of all cell types. A hyperplastic pancreas consisting of undifferentiated cells expressing Pdx1, Nkx6.1, and cell adhesion markers normally characterizing early pancreatic progenitor cells resulted. Differentiation was attenuated even as proliferation of the pancreatic cells slowed during late gestation, suggesting that the trophic effect of FGF10 was independent of its effects upon cell differentiation. The FGF10-positive pancreatic cells expressed Notch1 and Notch2, the Notch-ligand genes Jagged1 and Jagged2, as well as the Notch target gene Hes1. This activation of Notch is distinct from the previously recognized mechanism of lateral inhibition. These data suggest that FGF10 signaling serves to integrate cell growth and terminal differentiation at the level of Notch activation, revealing a novel second role of this key signaling system during pancreatic development.

Animals↗
PubMed2005

Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.

Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.

Amyloid Precursor Protein Secretases↗
PubMed2003

Differentiation of bone marrow cells into cells that express liver-specific genes in vitro: implication of the Notch signals in differentiation.

Bone marrow (BM) stem cells have been shown to differentiate into liver cells. It remains difficult to sort and culture BM stem cells, and the gene expression of liver-specific proteins in these cells has not been fully investigated. We used a negative selective magnetic cell separation system to obtain stem cell-enriched BM cells. The cells obtained were cultured with hepatocytes or with hepatocyte growth factor (HGF), and the differentiation of BM cells into cells expressing liver-specific genes, hepatocyte nuclear factor (HNF) 1alpha, cytokeratin (CK) 8, alpha-fetoprotein (AFP), and albumin was investigated by the reverse transcription-polymerase chain reaction. We also investigated the gene expressions of Notch receptor-1 (Notch-1) and its ligand Jagged-1 in BM cell differentiation. Sorted BM cells showed positive for Sca-1 (Ataxin-1) by immunofluorescence staining. Fluorescence activated cell sorter analysis showed that 32.6% of sorted BM cells had a high level of expression of the hematopoietic stem cell marker CD90 (Thy-1). When cultured with hepatocytes, these cells expressed the liver-specific genes HNF1alpha and CK8 on culture day 3, AFP and albumin on culture day 7. When cultured with HGF (20ng/ml), the cells expressed HNF1alpha on day 3 and CK8 on day 7. Gene expressions of Notch-1 and Jagged-1 were detected in cultured BM cells on day 3. These results suggest that the negative selective magnetic cell separation system is useful for the rapid preparation of stem cell-enriched BM cells, and that the Notch signaling pathway plays a role in BM cell differentiation into a hepatocyte lineage in vitro.

Animals↗
PubMed2003

Osteogenic differentiation of the mesenchymal progenitor cells, Kusa is suppressed by Notch signaling.

Notch receptor plays a crucial role in proliferation and differentiation of many cell types. To elucidate the function of Notch signaling in osteogenesis, we transfected the constitutively active Notch1 (Notch intracellular domain, NICD) into two different osteoblastic mesenchymal cell lines, KusaA and KusaO, and examined the changes of their osteogenic potentials. In NICD stable transformants (KusaA(NICD) and KusaO(NICD)), osteogenic properties including alkaline phosphatase activity, expression of osteocalcin and type I collagen, and in vitro calcification were suppressed. Transient transfection of NICD attenuated the promoter activities of Cbfa1 and Ose2 element. KusaA was capable of forming trabecular bone-like tissues when injected into mouse abdomen, but this in vivo bone forming activity was significantly suppressed in KusaA(NICD). Osteoclasts were induced in the KusaA-derived bone-like tissues, but lacked in the KusaA(NICD)-derived tissues. These results suggest that Notch signaling suppresses the osteoblastic differentiation of mesenchymal progenitor cells.

Animals↗
PubMed1995

Importance of notching and slurring of the resting QRS complex in the diagnosis of coronary artery disease.

Data on the correlation of coronary artery disease (CAD) and electrocardiographic findings are, except for Q waves, still controversial. The purpose of this study was to determine whether QRS complex notching and slurring (N&S) is of significant value as a diagnostic discriminator in the detection of CAD. This study comprised 500 consecutive patients aged between 24 and 81 years (mean, 53.4 years) who underwent coronary angiography because of chest pain. Patients were evaluated for CAD, angiographic evidence of myocardial infarction (MI), N&S, and abnormal Q waves. Of these 500 patients, 418 had CAD, and 370 of these had significant (> or = 70%) coronary artery obstruction. The remaining 82 patients had normal coronary arteries. The data revealed that the distribution of N&S in the patients with or without CAD was similar in both the inferior and limb leads (P > .05). But the percentage of N&S in more than two contiguous limb leads was higher in the patients with CAD than in the patients without CAD. Notching and slurring in at least one limb lead was found to be of no value in the diagnosis of MI, of wall motion abnormalities, and of significant obstruction. Notching and slurring in the anterior leads is more sensitive but less specific than abnormal Q waves in the same leads in the detection of significant obstruction, anterior MI, and anterior wall motion abnormalities. Notching and slurring in the anterior leads has as much importance as abnormal anterior Q waves in the detection of angiographic evidence of anterior infarct, of anterior wall motion abnormalities, and of significant coronary artery obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Blunt-edged, notched scalpel for cesarean incision.

BACKGROUND: Fetal penetrating injuries during cesarean delivery are rare but possible complications. We describe our findings from using a newly developed blunt-edged, notched scalpel to incise the uterine wall during cesarean delivery. INSTRUMENT: The scalpel was designed with a blunt edge and notches. The blunt edge did not penetrate the uterine wall, and thus fetal injury was prevented. The notched blade split the uterine muscle fibers when the entry incision was made. EXPERIENCE: We used this tool in 41 women with intact membranes who had uterine wall incisions during cesarean deliveries. There were no fetal injuries or major complications. CONCLUSION: Making uterine incisions with this new blunt-edged, notched scalpel is feasible, easy, and safe.

Cesarean Section↗
PubMed2000

Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos.

In vertebrates Notch signaling regulates cell fate decisions and boundary formation and it underlies several murine and human diseases. Gene targeting experiments point to key roles of Notch receptors, ligands, modulators and downstream targets in somitogenesis, neurogenesis and vascular development. Here we report the embryonic expression of the hairy-related basic helix-loop-helix gene HeyL in wild-type and Notch pathway mutant mice. We show that HeyL is strongly expressed in the presomitic mesoderm, the somites, the peripheral nervous system and smooth muscle of all arteries. Loss of HeyL expression at the level of nascent somites in Notch1 and Delta-like1 knockout mutants implicates HeyL as a Notch effector during somite formation. Furthermore, HeyL expression in vascular smooth muscle cells and in the thymus strikingly overlaps with that of Notch3, mutations of which underlie the CADASIL vascular disorder.

Animals↗
PubMed1998

Molecular characterization of the Notch homologue from the Australian sheep blowfly, Lucilia cuprina.

The Drosophila melanogaster Notch gene product as a receptor of intercellular signals and is central to cell fate specification. The Scalloped wings (Scl) gene is the homologue of Notch in the Australian sheep blowfly, Lucilia cuprina. An allele of Scl is thought to be involved in the modification of Darwinian fitness and bristle asymmetry in flies resistant to organophosphorous chemicals (OPs). As a first step towards the testing of this hypothesis we cloned and sequenced Scl. A full-length cDNA segment representing the mRNA of Scl is 8503 bp and encodes a protein of 2653 amino acids, which shares 73.6% identity with Notch. All functional motifs including EGF-like repeats, LNR repeats, cdc 10/ankyrin repeats, opa and PEST elements are present in the same order as in Notch and the sequence identities peak in these motifs. With respect to genomic structure, intron/exon boundaries are conserved but, in most cases, the Scl introns are larger. Sequence analysis of the upstream genomic region reveals that the gene has a TATA-less promoter. Consistent with a central role in embryogenesis and imaginal development, high levels of Scl expression were detected in the early embryonic and pupal stages.

Animals↗
PubMed1998

Correlating notch signaling with thymocyte maturation.

The Notch receptor and its ligands are involved in many developmental processes. They are highly expressed in the thymus and have been implicated in the CD4 versus CD8 lineage decision. We identified the constitutively active intracellular fragment of murine Notch-1 as capable of rendering thymomas resistant to glucocorticoid-induced apoptosis. This effect was confirmed in other T cell lines and in CD4+ CD8+ DP thymocytes. Activation of the Notch signaling pathway also upregulated a number of other markers that, like steroid resistance, correlate with DP maturation into both the CD4 and CD8 lineages. These results suggest that Notch signaling is critically involved in the maturation of DP thymocytes into both CD4+ and CD8+ SP thymocytes.

Animals↗
PubMed2004

Notch activation regulates the segregation and differentiation of rhombomere boundary cells in the zebrafish hindbrain.

During segmentation of the vertebrate hindbrain, a distinct population of boundary cells forms at the interface between each segment. Little is known regarding mechanisms that regulate the formation or functions of these cells. We have investigated a potential role of Notch signaling and find that in the zebrafish hindbrain, radical fringe is expressed in boundary cells and delta genes are expressed adjacent to boundaries, consistent with a sustained activation of Notch in boundary cells. Mosaic expression experiments reveal that activation of the Notch/Su(H) pathway regulates cell affinity properties that segregate cells to boundaries. In addition, Notch signaling correlates with a delayed neurogenesis at hindbrain boundaries and is required to inhibit premature neuronal differentiation of boundary cells. These findings reveal that Notch activation couples the regulation of location and differentiation in hindbrain boundary cells. Such coupling may be important for these cells to act as a stable signaling center.

Animals↗
PubMed2003

Expression of Notch pathway genes in the embryonic mouse metanephros suggests a role in proximal tubule development.

The interaction of neighboring cells via Notch signalling leads to cell fate determination, differentiation and patterning of highly organized tissues. Mice with targeted disruption of genes from the Notch signal transduction pathway display defects in the developing somites, neurogenic structures, blood vessels, heart and other organs. Recent studies have added requirements for Notch signalling during kidney, pancreas and thymus morphogenesis. Here, we describe the expression of all four receptors (Notch1-4), the five transmembrane ligands (Dll1, 3, 4, Jag1 and Jag2), intracellular effectors (the Hey genes) and extracellular modulators (Lfng, Mfng, Rfng) in the developing mouse metanephros. Our results point to a Lfng-dependent role for Notch signalling in the development of nephron segments, especially the proximal tubules.

Animals↗
PubMed1999

Notch signalling pathway mediates hair cell development in mammalian cochlea.

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.

Animals↗