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At least 217 records · Page 12Linked to original sources
PubMed2002

[Sensitivity of the neurons in the auditory inferior colliculus of mice to the direction of the shift of broadband spectral notch noise].

Series of a notch noise with regular shifts of the notch center frequency: one--from low frequencies to high frequencies and the other--from high frequencies to the low, were synthesized. The notch noise series imitated sound source vertical moving. Single neuron's responses of inferior colliculus of the house mouse (Mus musculus) to the notch-noises altered with notch central frequency varying through excitatory and inhibitory frequency response areas in neurones' receptive fields. The neural responses alteration to the notch noise varying depended on the bandwidth of notch. Disinhibition in inhibitory side band could be higher if the notch overlying the inhibitory areas followed the notch overlying the excitatory areas. The data obtained make it possible to consider the excitatory and inhibitory interaction as a mechanism of neural sensitivity to the notch moving direction. Neurones' response set could provide information about sound source moving over auditory space.

Acoustic Stimulation↗
PubMedDate not supplied

Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture.

The transduction of Notch signal plays an intricate role in cell differentiation and pathogenesis of haematological malignancies as well as in certain congenital conditions. The functionality of Notch signalling was tested using HES1 gene activation. SEL1 gene product has been postulated to be a negative regulator of Notch signalling. We investigated the relationship between Notch signalling and the expression of SEL1L gene in a number of leukaemia and lymphoma cells in culture. The cell lines could be separated into two groups. Group 1 contained lymphoma cell lines in which Notch signalling was intact; of these 4 cell lines were SEL1L+/HES1- and 3 SEL1L-/HES1-. Notch signalling was not subverted by EBNA2 expression in these lymphoma cells. In Group 2 cell lines Notch signalling was constitutively active but 6 out of 7 cell lines expressed SEL1L at high levels. In summary, a majority of cell lines of both groups express SEL1L and no inverse relationship is evident between SEL1L expression and the status of Notch signalling. The present investigation therefore suggests that SEL1L may not exert a negative regulatory influence on Notch signalling. No genomic alterations affecting SEL1L were detected either in the lymphoma or T-ALL cell lines tested. Taken together the present findings do not support the postulated negative regulatory role for SEL1L in Notch signalling.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Notch ligands, Delta-1 and Delta-4 suppress the self-renewal capacity and long-term growth of two myeloblastic leukemia cell lines.

The self-renewal and differentiation of hematopoietic progenitors are regulated by the interaction between Notch receptors and Notch ligands. Since AML originates from dysregulated hematopoietic progenitors, some abnormalities in the Notch system may be involved in the abnormal proliferation of AML cells. However, the significance of the Notch system in AML is not known. We examined the functional roles of Notch activation on the in vitro growth of seven human AML cell lines using three kinds of recombinant Notch ligand proteins, Jagged-1, Delta-1 and Delta-4. The ligands significantly affected the growth of two cell lines. In TMD7 cells, Delta proteins promoted the short-term growth, however, suppressing the self-renewal capacity and long-term growth. In OCI/AML-6 cells, Delta proteins suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. We additionally found that Notch ligands needed to be immobilized on culture wells to affect the cells. These findings were in contrast to our hypothesis that Notch activation in AML cells leads to excessive self-renewal capacity and proliferation. If the Notch system in AML cells is precisely understood, the control of Notch activation will become a novel therapeutic approach for AML.

Adaptor Proteins, Signal Transducing↗
PubMed2003

[Significance of early diastolic notch in the prognosis of unfavorable pregnancy outcome].

OBJECTIVE: The appraisal of the sensitivity and the specificity of unilateral and bilateral or severe early diastolic notchs for prognosis of unfavorable pregnancy outcomes. PATIENTS AND METHODS: The clinical study was performed in Kaunas University of Medicine Hospital. Two hundred thirty one patients with pregnant chronic hypertension or pre-eclampsia and 229 healthy pregnant women were involved into the study. The occurrence of early diastolic notch was compared between the groups. The sensitivity and specificity of unilateral and bilateral or severe early diastolic notches for prognosis of unfavorable pregnancy outcome was evaluated. RESULTS: The sensitivity of bilateral early diastolic notch for prognosis of various unfavorable pregnancy outcomes was 64.5-70.6%, and the specificity was 71.9-79.7%. The sensitivity of unilateral early diastolic notch for prognosis of unfavorable pregnancy outcome was 78-90%, the specificity was 50-58%. The sensitivity of severe diastolic notch was 20-29.4%, and the specificity was 91-95.2%. CONCLUSIONS: The finding of bilateral early diastolic notches in the uterine artery Doppler velocimetry waveforms is a sensitive method for prognosis of unfavorable pregnancy outcomes in hypertensive women. Severe diastolic notch is more specific, but less sensitive method in comparison with bilateral early diastolic notches. The unilateral early diastolic notch has low specificity for prognosis of unfavorable pregnancy outcome.

Adult↗
PubMed1992

Effects of notch noise bandwidth on the auditory brainstem response to clicks.

The effects of notch width of notch masking noise on the auditory brainstem response (ABR) were investigated with ten normal-hearing subjects. Wave V latencies and amplitudes were measured to a click in quiet and in the presence of noise with notches centered around 1000 Hz and 4000 Hz. Notch width was either 0.5, 1.0, 1.5, 2.0, or 2.5 octaves. A 95 dB SPL broadband noise was necessary to mask a 65 dB nHL click at an effective level of 73 dB nHL. All ten subjects at both 1000 Hz and 4000 Hz yielded identifiable responses for the click in quiet and for the 2.5 octave and 2.0 octave conditions, and eight or nine subjects responded to the 1.5 octave notch noise. In contrast, no responses were observed to the 0.5 octave condition, and only three or four subjects responded to the 1.0 octave notch noise. These findings suggest that when ABRs are obtained to 65 dB nHL clicks in notch noise, the notch width should exceed 1.0 octave. Moreover, because of the relatively low amplitudes elicited with the 1.5 octave bandwidth, it appears preferable to select notches that are 2.0 to 2.5 octaves wide. Considering the wide bandwidth required, the high noise levels necessary to mask clicks, high ABR thresholds, and the difficulty setting the signal-to-noise ratio, it appears that tonepips are more promising than clicks in notch noise for assessing frequency specific ABRs.

Acoustic Stimulation↗
PubMed2004

[Suppressive effect of Notch signal activation on apoptosis of multiple myeloma cells].

The proliferation and apoptosis of multiple myeloma (MM) cells were regulated by bone marrow microenvironments in which Notch signal plays important role in mediating cell-cell communication. However, the regulatory effect of Notch signal on the proliferation and apoptosis of multiple myeloma cells remains unclear. In this study, regulatory effect of Notch signal on the apoptosis of MM cells induced by DMS (N, N-dimethylsphingosine) was investigated. RT-PCR was used to identify the expression of Notch receptor and related molecules such as Dll-1, Jagged-1, Deltex-1 in MM cell lines. The intracellular domain of Notch (ICN), active form of Notch, was transferred into MM cells by retrovirus. The apoptosis of MM cells was determined by trypan blue exclusion tests and TdT-mediated dUTP nick end labeling (TUNEL) assay. The results showed that multiple myeloma cells expressed the Notch-1 and its related molecules. Notch activated multiple myeloma cell lines were obtained. Activation of Notch protected the multiple myeloma cells from the apoptosis induced by DMS,which was determined by cell viability and TUNEL assay. In conclusion, Notch signal suppressed the apoptosis of multiple myeloma cells and would possibly be a novel therapeutic target.

Apoptosis↗
PubMed1992

Systolic or diastolic notch in uterine artery blood flow velocity waveforms in hypertensive pregnant patients: relationship to outcome.

To identify the relationship between a systolic or diastolic notch in uterine artery flow velocity waveforms and pregnancy outcome, we studied 140 hypertensive pregnant women with transvaginal, image-directed pulsed Doppler ultrasound. The subjects were classified according to the presence or absence of a systolic or diastolic notch. In 14 with a systolic and 25 with a diastolic notch, the resistance indexes in the uterine arteries on both sides of the uterus were significantly higher than in 101 subjects without a notch. Those with notches had significantly higher rates of fetal growth retardation and cesarean delivery because of fetal distress. Significantly more infants born to women with a notch spent longer than 48 hours in the neonatal intensive care unit. Subjects with a systolic notch also had significantly higher rates of abnormal fetal heart rate patterns during labor and low Apgar scores at 5 minutes. Fifty-one women with elevated resistances indexes in both uterine arteries were divided into two groups according to the resistance index in the umbilical artery. Each group was subdivided according to the presence or absence of a systolic or diastolic notch in the uterine artery flow velocity waveforms. In the group with a normal resistance index in the umbilical artery, five women had growth-retarded fetuses when a notch was present (N = 8), compared with none in women without a notch (N = 11) (P less than .005). The respective figures for the group with abnormal umbilical artery resistance indexes were 14 of 19 (73.7%) and two of 13 (15.4%) (P less than .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Arteries↗
PubMed1997

Dimensions of the intercondylar notch of the knee.

This study evaluates the three-dimensional contour of the intercondylar notch of the knee along its entire length. Forty-one distal femora, from human cadavers with a mean age of 45 years (range: 23 to 70 years) at the time of death were studied. The specimens were selected for the absence of previous surgery or degenerative changes including osteophyte formation. Measurements were taken from a cast of the distal femur. Transverse sections of the cast were cut every 3 mm in a plane perpendicular to the long axis of the femur. Within this plane, the epicondylar width, the condylar height, the notch height, and the minimum and maximum width of the notch were measured. The ratios between these measurements were calculated and subjected to analysis of variance. The notch width increased gradually from a mean of 1.8 cm at the distal aspect to a mean of 2.3 cm at the most proximal portion. The notch height increased from a mean value of 1.8 cm at the distal-most portion to a maximum of 2.4 cm at 1.8 cm from the distal-most portion of the notch. The height then decreased to a mean value of 1.3 cm at the most proximal portion of the notch. The epicondylar width:notch width ratio ranged from 4.70 distally to 4.25 proximally. These results indicate that the notch is narrowest distally and widens proximally, and the notch height is greatest in the midportion and decreases proximally and distally.

Adult↗
PubMed1998

The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells.

We examined the expression of two members of the Notch family, Notch-1 and Notch-2, and one Notch ligand, Jagged-1, in hematopoietic cells. Both Notch-1 and Notch-2 were detected in murine marrow precursors (Lin-Sca-1+c-kit+). The Notch ligand, Jagged-1, was not detected in whole marrow or in precursors. However, Jagged-1 was seen in cultured primary murine fetal liver stroma, cultured primary murine bone marrow stroma, and in stromal cell lines. These results indicate a potential role for Notch-Notch ligand interactions in hematopoiesis. To further test this possibility, the effect of Jagged-1 on murine marrow precursor cells was assessed by coculturing sorted precursor cells (Lin-Sca-1+c-kit+) with a 3T3 cell layer that expressed human Jagged-1 or by incubating sorted precursors with beads coated with the purified extracellular domain of human Jagged-1 (Jagged-1(ext)). We found that Jagged-1, presented both on the cell surface and on beads, promoted a twofold to threefold increase in the formation of primitive precursor cell populations. These results suggest a potential use for Notch ligands in expanding precursor cell populations in vitro.

3T3 Cells↗
PubMed2004

Notch function in the vasculature: insights from zebrafish, mouse and man.

Vascular development entails multiple cell-fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell-fate determination in a variety of cell types. The finding that Notch genes are robustly expressed in the vasculature suggests roles for Notch in guiding endothelial and associated mural cells through the myriad of cell-fate decisions needed to form the vasculature. In fact, mice with defects in genes encoding Notch, Notch ligands, and components of the Notch signaling cascade invariably display vascular defects. Human Notch genes are linked to Alagille's Syndrome, a developmental disorder with vascular defects, and CADASIL, a cerebral arteriopathy. Studies in zebrafish, mice and humans indicate that Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. Here, we will focus on established functions for Notch in vascular remodeling and arterial/venous specification and more speculative roles in vascular homeostasis and organ-specific angiogenesis.

Animals↗
PubMed2004

Coexpression of Cux-1 and Notch signaling pathway components during kidney development.

Cux-1 is the murine homologue of the Drosophila gene cut, which is required for cellular differentiation in several tissues, including the wing margin and Malpighian tubule. Mammalian cut proteins function as cell cycle-dependent transcriptional repressors in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. However, little is known about the regulation of Cux-1. In Drosophila, multiple genetic interactions between Cut and the Notch and Wingless signaling pathways occur during wing development. To begin to determine whether Cux-1 regulation by the Notch signaling pathway is conserved in mammals, we compared the expression patterns of Cux-1, the murine Notch receptors (Notch 1-4), and the murine ligands (Jagged 1, Jagged 2, and Delta 1) during murine embryogenesis and kidney development. In this report, we demonstrate that Cux-1 expression overlaps with that of Notch signaling pathway components in multiple tissues during embryonic development. In the developing kidney, Cux-1 expression overlaps with that of Notch pathway components in the condensing mesenchyme, in pretubular aggregates (comma and S-shaped bodies), and in the presumptive podocytes of capillary loop stage glomeruli. Furthermore, Cux-1 was significantly up-regulated in the rat kidney epithelial cell line RKE expressing a constitutively active Notch 1, and this finding was associated with a reduction of p27. Moreover, Cux-1 interacts with the Groucho homolog TLE-4, a corepressor recruited by Notch effector proteins. Taken together, these results suggest that Cux-1 may function in the context of the Notch signaling pathway in multiple tissues during mammalian embryogenesis.

Animals↗
PubMed2002

Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL.

Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain. Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus. Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3. The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.

Animals↗
PubMed2005

A DNA transcription code for cell-specific gene activation by notch signaling.

BACKGROUND: Cell-specific gene regulation is often controlled by specific combinations of DNA binding sites in target enhancers or promoters. A key question is whether these sites are randomly arranged or if there is an organizational pattern or "architecture" within such regulatory modules. During Notch signaling in Drosophila proneural clusters, cell-specific activation of certain Notch target genes is known to require transcriptional synergy between the Notch intracellular domain (NICD) complexed with CSL proteins bound to "S" DNA sites and proneural bHLH activator proteins bound to nearby "A" DNA sites. Previous studies have implied that arbitrary combinations of S and A DNA binding sites (an "S+A" transcription code) can mediate the Notch-proneural transcriptional synergy. RESULTS: By contrast, we show that the Notch-proneural transcriptional synergy critically requires a particular DNA site architecture ("SPS"), which consists of a pair of specifically-oriented S binding sites. Native and synthetic promoter analysis shows that the SPS architecture in combination with proneural A sites creates a minimal DNA regulatory code, "SPS+A", that is both sufficient and critical for mediating the Notch-proneural synergy. Transgenic Drosophila analysis confirms the SPS orientation requirement during Notch signaling in proneural clusters. We also present evidence that CSL interacts directly with the proneural Daughterless protein, thus providing a molecular mechanism for this synergy. CONCLUSIONS: The SPS architecture functions to mediate or enable the Notch-proneural transcriptional synergy which drives Notch target gene activation in specific cells. Thus, SPS+A is an architectural DNA transcription code that programs a cell-specific pattern of gene expression.

Animals↗
PubMed2006

Lethal giant discs, a novel C2-domain protein, restricts notch activation during endocytosis.

The Notch signaling pathway plays a central role in animal growth and patterning, and its deregulation leads to many human diseases, including cancer. Mutations in the tumor suppressor lethal giant discs (lgd) induce strong Notch activation and hyperplastic overgrowth of Drosophila imaginal discs. However, the gene that encodes Lgd and its function in the Notch pathway have not yet been identified. Here, we report that Lgd is a novel, conserved C2-domain protein that regulates Notch receptor trafficking. Notch accumulates on early endosomes in lgd mutant cells and signals in a ligand-independent manner. This phenotype is similar to that seen when cells lose endosomal-pathway components such as Erupted and Vps25. Interestingly, Notch activation in lgd mutant cells requires the early endosomal component Hrs, indicating that Hrs is epistatic to Lgd. These data suggest that Lgd affects Notch trafficking between the actions of Hrs and the late endosomal component Vps25. Taken together, our data identify Lgd as a novel tumor-suppressor protein that regulates Notch signaling by targeting Notch for degradation or recycling.

Amino Acid Sequence↗
PubMed2006

Notch signaling in the regulation of tumor angiogenesis.

The Notch signaling pathway is conserved in vertebrates and invertebrates and is involved in many developmental processes. Notch receptors and ligands are expressed on the cell surface enabling interactions between adjacent cells upon receptor-ligand binding. Notch signaling molecules have an important well-documented role in vascular development, differentiation, proliferation, apoptosis and tumorigenesis. Recently, several groups have identified the importance of Notch signaling in tumor angiogenesis. Notch activity increases specifically in tumor endothelium and in various tumors types and, in some studies, Notch signaling suppresses angiogenic processes. Because the Notch signaling pathway can mediate communication between various cell types in the tumor microenvironment, interactions between tumor cells and endothelial cells might promote angiogenesis, therefore targeting the Notch pathway might provide a novel strategy for anti-angiogenic therapies. Here, we discuss recent insights of Notch signaling in tumor angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2005

A Fringe-modified Notch signal affects specification of mesoderm and endoderm in the sea urchin embryo.

Fringe proteins are O-fucose-specific beta-1,3 N-acetylglucosaminyltransferases that glycosylate the extracellular EGF repeats of Notch and enable Notch to be activated by the ligand Delta. In the sea urchin, signaling between Delta and Notch is known to be necessary for specification of secondary mesenchyme cells (SMCs). The Lytechinus variegatus Fringe homologue is expressed in both the signaling and receiving cells during this first Delta-Notch signal. Perturbation of Fringe expression through morpholino antisense oligonucleotide (MO) injection results in fewer SMCs but also causes decreased and delayed archenteron invagination. Partial endoderm specification occurs but expression of some endoderm genes is compromised. The data are consistent with a Fringe-requiring Notch signal as one upstream component of archenteron morphogenesis. Finally, Fringe perturbations result in more severe phenotypes than those previously reported for Notch dominant-negative (LvN(neg)) injections or reported here for Notch MO (NMO) injections. Injecting a combination of LvN(neg) and NMO results in a more severe phenotype than either treatment alone, and this combination phenocopies the fringe MO embryos. Taken together, the results show that Fringe is necessary both for maternal and zygotic Notch signals, and these Notch signals affect specification of mesoderm and endoderm.

Animals↗
PubMed2006

Notch pathway repression by vestigial is required to promote indirect flight muscle differentiation in Drosophila melanogaster.

Drosophila dorsal longitudinal muscles develop during metamorphosis by fusion of myoblasts with larval templates. It has been shown that both vestigial and Notch are crucial for correct formation of these muscles. We investigated the relationship between vestigial and the Notch pathway during this process. Using Enhancer of Split Region Transcript m6 gene expression as a reporter of Notch pathway activity, we were able to demonstrate that this pathway is only active in myoblasts. Moreover, close examination of the cellular location of several of the main actors of the N pathway (Notch, Delta, neuralized, Serrate, Mind bomb1 and fringe) during dorsal longitudinal muscle development enabled us to find that Notch receptor can play multiple roles in adult myogenesis. We report that the locations of the two Notch ligands (Delta and Serrate) are different. Interestingly, we found that fringe, which encodes a glycosyltransferase that modifies the affinity of the Notch receptor for its ligands, is expressed in muscle fibers and in a subset of myoblasts. In addition, we demonstrate that fringe expression is essential for Notch pathway inhibition and muscle differentiation. Lastly, we report that, in vestigial mutants, fringe expression is lost, and when fringe is overexpressed, a significant rescue of indirect flight muscle degeneration is obtained. Altogether, our data show that a vestigial-differentiating function is achieved through the inhibition of the Notch pathway.

Animals↗
PubMed2003

Down-regulation of Notch target gene expression by Suppressor of deltex.

In Drosophila, Suppressor of deltex (Su(dx)) mutations display a wing vein gap phenotype resembling that of Notch gain of function alleles. The Su(dx) protein may therefore act as a negative regulator of Notch but its activity on actual Notch signalling levels has not been demonstrated. Here we show that Su(dx) does regulate the level of Notch signalling in vivo, upstream of Notch target genes and in different developmental contexts, including a previously unknown role in leg joint formation. Overexpression of Su(dx) was capable of blocking both the endogenous activity of Notch and the ectopic Notch signalling induced by the overexpression of Deltex, an intracellular Notch binding protein. In addition, using the conditional phenotype of the Su(dx)(sp) allele, we show that loss of Su(dx) activity is rapidly followed by an up-regulation of E(spl)mbeta expression, the immediate target of Notch signal activation during wing vein development. While Su(dx) adult wing vein phenotypes are quite mild, only affecting the distal tips of the veins, we show that the initial consequence of loss of Su(dx) activity is more severe than previously thought. Using a time-course experiment we show that the phenotype is buffered by feedback regulation illustrating how signalling networks can make development robust to perturbation.

Alleles↗